Supplementary Information

Fluorine in fragrances: Exploring the difluoromethylene (CF2) group as a

conformational constraint in macrocyclic musk lactones

Michael J. Corra, Rodrigo A. Cormanichb, Cortney N. von Hahmanna, Michael Bühla, David B.

Cordesa, Alexandra M. Z. Slawina and David O’Hagan.a*

aSchool of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK. E mail: do1@st-andrews.ac.uk

bChemistry Institute, University of Campinas, Campinas, SP, 13083-970, Brazil.

General

All reagents were purchased from commercial suppliers and were used without further

purification unless otherwise stated. Tetrahydrofuran, dichloromethane, toluene and diethyl

ether were dried and deoxygenated with an MBraun SPS-800 solvent purification system and

the moisture content of the solvents was analysed using a Karl Fischer coulometer (Metler

Toledo DL32). Dry DMF was purchased from Merck and was used as purchased.

Infra-red spectra were recorded on a Perkin Elmer Spectrum GX FT-IR system. Proton NMR

(1H), carbon NMR (13C) and fluorine NMR (19F) were recorded on a Bruker Advance 500

(500 MHz), Bruker Avance II (400 MHz) or a Bruker Avance 300 (300 MHz) spectrometer.

Fluorine NMR were were also recorded as proton decoupled (19F{1H}). Using a deptq

sequence or an HSQC experiment with multiplicity editing, the 13C NMR signals were

assigned to CH3, CH2, CH and C. The NMR experiments were carried out in

deuterochloroform (CDCl3). The chemical shifts () are quoted in parts per million (ppm).

Multiplicities are abbreviated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b,

broad for the 1H NMR, 19F NMR, 19F{1H} NMR and 13C NMR spectra. Coupling constants

are reported in Hertz (Hz).

High and low resolution mass spectra were recorded at the EPSRC National Mass

Spectrometry Service, Swansea or at the University of St Andrews on a Waters Micromass

LCT time of flight mass spectrometer coupled to a Waters 2975 HPLC system. Optical

rotation values were recorded on a Perkin Elmer Model 341 Polarimeter using a Na/Hal lamp

(589 nm) at 20 C in a 1 dm polarimeter cell and are given in 10-1 deg cm2 g-1. A kdScientific

syringe pump (model #KDS-100-CE) was used when required.

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2015

mailto:do1@st-andrews.ac.uk

Flash chromatography was performed using silica gel 60 (200-400 mesh). Thin layer

chromatography (TLC) was performed using aluminium sheets of silica gel 60 F254 and was

visualised under a Mineralight model UVGL-58 lamp (254 nm). The plates were developed

with acidic methanolic vanillin solutions, ethanolic phosphomolybdic acid solutions or basic

potassium permanganate solutions.

The IUPAC names of some compounds were obtained using Reaxys® (www.reaxys.com).

List of Chemical Abbreviations

4-DMAP 4-Dimethylaminopyridine9-BBN 9-Borabicyclo(3.3.1)nonaneBAIB Bis(acetoxy)iodobenzeneDAST Diethylaminosulfur trifluorideDCM DichloromethaneDDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinoneDME DimethoxyethaneDMP Dess-Martin PeriodinaneDMSO N,N-DimethylsulfoxidemCPBA m-Chloroperbenzoic acidNaHMDS sodium bis(trimethylsilyl)amide/ sodium hexamethyldisilazidenBuLi n-ButyllithiumPMB-Cl p-Methoxybenzyl chlorideTBAI Tetrabutylammonium iodideTEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxylTHF Tetrahydrofuran

Hex-5-enoic acid 191

HO

O

19

Hydrogen peroxide (30% in water, 227 mL, 2 mol, 2.0 eq) was added over 30 min to a

solution of cyclohexanone 18 (104 mL, 1 mol, 1.0 eq) in methanol (100 mL) at r.t. The

mixture was then added to a solution of iron (II) sulfate heptahydrate (278 g, 1 mol, 1.0 eq)

and copper (II) sulfate pentahydrate (250 g, 1 mol, 1.0 eq) in water (1.8 L) over 2 h. The

reaction mixture was extracted with diethyl ether (3 x 200 mL). The combined ether layers

were washed with sodium hydroxide solution (20%, 3 x 100 mL). The combined aqueous

layers were acidified to pH 2 with sulfuric acid solution (20%). The aqueous layer was

extracted with diethyl ether (3 x 200 mL). The combined organic layers were dried over

anhydrous Na2SO4 and the solvent was removed in vacuo. Purification by distillation (75 C

at 0.1 mbar) gave hex-5-enoic acid 19 (22.4 g, 20%) as a colourless oil; 1H NMR (400 MHz,

CDCl3) = 1.76 (2H, tt, J(H,H)= 7.6, 7.5 Hz, CH2), 2.10-2.16 (2H, m, CH2), 2.38 (2H, t,

J(H,H)= 7.6 Hz, CH2), 4.99-5.08 (2H, m, CH2), 5.74-5.84 (1H, m, CH); 13C NMR (100 MHz,

CDCl3) = 23.9 (CH2), 33.1 (CH2), 33.3 (CH2), 115.8 (CH2), 137.7 (CH), 179.4 (CO); MS

(ESI) 113 (100) [M-H]-; HRMS: m/z calcd for C6H9O2 [M-H]-: 113.0608; found: 113.0604.

(4R)-3-(Hex-5-enoyl)-5,5-dimethyl-4-(propan-2-yl)-1,3-oxazolidin-2-one 21

NO

O O

21

nBuLi (1.6 M in hexanes, 126 mL, 200.4 mmol, 1.2 eq) was added to a solution of (4R)-5,5-

dimethyl-4-(propan-2-yl)-1,3-oxazolidin-2-one 20 (26.3 g, 167 mmol, 1.0 eq) in dry THF

(500 mL) at -78 C under argon. In a separate flask, pivaloyl chloride (27 mL, 217.1 mmol,

1.3 eq) and triethylamine (40 mL, 283.9 mmol, 1.7 eq) were added to a solution of hex-5-

enoic acid 19 (22.9 g, 200.4 mmol, 1.2 eq) in dry THF (200 mL) at 0 C under argon and

stirred for 30 min. The oxazolidinone solution was added to the mixed anhydride via cannula

and stirred at 0 C for 30 min, then warmed to r.t. and stirred for 1.5 h. The reaction mixture

was quenched with sat. NH4Cl solution (500 mL) and extracted with ethyl acetate (2 x 500

mL). The combined organic layers were washed with sat. NaHCO3 solution (500 mL), sat.

NH4Cl solution (500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and the solvent

was removed in vacuo. Purification by column chromatography (EtOAc/Pet. ether 1:9) gave

(4R)-3-(hex-5-enoyl)-5,5-dimethyl-4-(propan-2-yl)-1,3-oxazolidin-2-one 21 (39.5 g, 93 %) as

a colourless oil; [α]D -30.6 (c 1.46, CHCl3) [lit.2 (4S)-21 [α]D +33.1 (c 1.0, CHCl3)]; 1H

NMR (500 MHz, CDCl3) = 0.94 (3H, d, J(H,H)= 6.8 Hz, CH3), 1.02 (3H, d, J(H,H)= 7.0

Hz, CH3), 1.37 (3H, s, CH3), 1.51 (3H, s, CH3), 1.72-1.86 (2H, m, CH2), 2.11-2.16 (3H, m,

CH2, CH), 2.89 (1H, ddd, J(H,H)= 16.7, 8.6, 6.4 Hz, CHAHB), 3.02 (1H, ddd, J(H,H)= 16.7,

8.6, 6.4 Hz, CHAHB), 4.15 (1H, d, J(H,H)= 3.3 Hz, CH), 5.02 (2H, dddd, J(H,H)= 31.3, 16.7,

3.3, 1.7 Hz, CH2), 5.77-5.85 (1H, m, CH); 13C NMR (125 MHz, CDCl3) = 17.3 (CH3), 21.6

(CH3), 21.7 (CH3), 24.0 (CH2), 29.0 (CH3), 29.8 (CH), 33.3 (CH2), 35.0 (CH2), 66.4 (CH),

82.9 (C), 115.5 (CH2), 138.1 (CH), 153.8 (CO), 173.9 (CO); IR (thin film) (cm-1) = 2975,

2934, 1780, 1702, 1641, 1465, 1375, 1363, 1315, 1279, 1220, 1172, 1122, 913; MS (ESI)

529 (35) [2M+Na]+, 276 (100) [M+Na]+, 254 (45) [M+H]+; HRMS: m/z calcd for

C14H23N1Na1O3 [M+Na]+: 276.1570; found: 276.1562.

(4R)- 5,5-Dimethyl-3-((2R)-methylhex-5-enoyl)-4-(propan-2-yl)-1,3-oxazolidin-2-one 22

NO

O O

22

NaHMDS (1.0 M in THF, 120 mL, 120 mmol, 1.1 eq) was added to a solution of (4R)-3-

(hex-5-enoyl)-5,5-dimethyl-4-(propan-2-yl)-1,3-oxazolidin-2-one 21 (27.6 g, 109.1 mmol,

1.0 eq) in dry THF (340 mL) at -78 C under argon and stirred at -78 C for 1 h. Iodomethane

(34 mL, 546 mmol, 5.0 eq) was added and the reaction mixture was stirred at -78 C for 1 h,

then warmed to r.t. and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl

solution (250 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic

layers were washed with sat. NaHCO3 solution (250 mL), sat. NH4Cl solution (250 mL) and

brine (250 mL), dried over anhydrous Na2SO4 and the solvent was removed in vacuo.

Purification by column chromatography (EtOAc/Pet. ether 1:9) gave (4R)-5,5-dimethyl-3-

((2R)-methylhex-5-enoyl)-4-(propan-2-yl)-1,3-oxazolidin-2-one 22 (26.9 g, 92%) as a white

solid as a single diastereoisomer by 1H NMR analysis; mp 44-46 C; [α]D -52.8 (c 1.23,

CHCl3) [lit.2 (2S,4S)-22 [α]D +51.4 (c 1.0, CHCl3)]; 1H NMR (500 MHz, CDCl3) = 0.96

(3H, d, J(H,H)= 6.8 Hz, CH3), 1.02 (3H, d, J(H,H)= 6.9 Hz, CH3), 1.27 (3H, d, J(H,H)= 6.8

Hz, CH3), 1.38 (3H, s, CH3), 1.46-1.52 (1H, m, CH2), 1.52 (3H, s, CH3), 1.85-1.92 (1H, m,

CH2), 2.04-2.09 (2H, m, CH2), 2.11-2.18 (1H, m, CH), 3.75-3.82 (1H, m,CH), 4.19 (1H, d,

J(H,H)= 3.3 Hz, CH), 4.98 (2H, dddd, J(H,H)= 29.2, 17.1, 3.3, 1.5 Hz, CH2), 5.74-5.82 (1H,

m, CH); 13C NMR (125 MHz, CDCl3) = 17.1 (CH3), 18.7 (CH3), 21.6 (CH3), 21.8 (CH3),

28.9 (CH3), 29.8 (CH), 31.9 (CH2), 32.4 (CH2), 37.5 (CH), 66.3 (CH), 82.8 (C), 115.2 (CH2),

138.4 (CH), 153.4 (CO), 177.7 (CO); IR (thin film) (cm-1) = 2976, 1774, 1700, 1362, 1266,

1173, 1095, 742; MS (ESI) 557 (30) [2M+Na]+, 290 (100) [M+Na]+, 268 (40) [M+H]+;

HRMS: m/z calcd for C15H25N1Na1O3 [M+Na]+: 290.1727; found: 290.1720.

(2R)-2-Methylhex-5-en-1-ol 23

HO

23

Lithium aluminium hydride (4.6 g, 122.1 mmol, 4.0 eq) was added to a solution of (4R)-5,5-

dimethyl-3-((2R)-methylhex-5-enoyl)-4-(propan-2-yl)-1,3-oxazolidin-2-one 22 (8.2 g, 30.5

mmol, 1.0 eq) in dry diethyl ether (250 mL) at 0 C under argon and stirred for 2 h. The

reaction mixture was quenched with water (10 mL). Sodium hydroxide solution (2 N, 10 mL)

was added, followed by water (10 mL). The resulting white solid was filtered and the filtrate

was collected. The solvent was removed in vacuo. Purification by column chromatography

using silica gel (EtOAc/Pet. ether 1:9) gave (2R)-2-methylhex-5-en-1-ol 23 (2.29 g, 66%) as

a colourless oil; [α]D +10.0 (c 1.05, CHCl3), lit.3 [α]D +9.1 (c 3.03, CHCl3); 1H NMR (500

MHz, CDCl3) = 0.94 (3H, d, J(H,H)= 6.7 Hz, CH3), 1.18-1.26 (1H, m, CHAHB), 1.41 (1H,

bs, OH), 1.49-1.56 (1H, m, CHAHB), 1.61-1.72 (1H, m, CH), 2.02-2.18 (2H, m, CH2), 3.45

(1H, dd, J(H,H)= 10.5, 6.4 Hz, CHAHB), 3.52 (1H, dd, J(H,H)= 10.6, 5.8 Hz, CHAHB), 4.94-

5.05 (2H, m, CH2), 5.78-5.86 (1H, m, CH); 13C NMR (125 MHz, CDCl3) = 16.6 (CH3),

31.4 (CH2), 32.5 (CH2), 35.4 (CH), 68.4 (CH2), 114.6 (CH2), 139.1 (CH); IR (thin film)

(cm-1) = 3348, 2956, 2925, 2875, 1641, 1458, 1039, 994, 910, 741; MS (CI) 115 (100)

[M+H]+; HRMS: m/z calcd for C7H15O1 [M+H]+: 115.1117; found: 115.1115.

(((2R)-2-Methylhex-5-en-1-ol)oxy)methyl)benzene 11

BnO

11

A solution of (2R)-2-methylhex-5-en-1-ol 23 (2.19 g, 19.2 mmol, 1.0 eq) in dry 1,2-

dimethoxyethane (20 mL) was added to a suspension of sodium hydride (60% in oil, 1.0 g,

24.9 mmol, 1.3 eq) in dry 1,2-dimethoxyethane (20 mL) at r.t. under argon. The reaction

mixture was stirred for 10 min, then benzyl bromide (2.7 mL, 23.0 mmol, 1.2 eq) was added

and the reaction mixture was stirred for 75 min. The reaction mixture was heated at reflux for

20 min, then cooled to r.t. and stirred for 18 h. HCl solution (2 N, 1 mL) was added and the

solvent was removed in vacuo. Purification by column chromatography using silica gel

(EtOAc/Pet. ether 1:19) gave (((2R)-2-methylhex-5-en-1-ol)oxy)methyl)benzene 11 (3.68 g,

94%) as a colourless oil; [α]D -2.7 (c 1.20, CHCl3) [lit.4 (2S)-11 [α]D +2.6 (c 6.2, CHCl3)]; 1H NMR (500 MHz, CDCl3) = 0.95 (3H, d, J(H,H)= 6.8 Hz, CH3), 1.19-1.27 (1H, m,

CHAHB), 1.53-1.60 (1H, m, CHAHB), 1.76-1.86 (1H, m, CH), 2.01-2.17 (2H, m, CH2), 3.28

(1H, dd, J(H,H)= 9.0, 6.6 Hz, CHAHB), 3.35 (1H, dd, J(H,H)= 9.0, 6.0 Hz, CHAHB), 4.50

(1H, d, J(H,H)= 12.3 Hz, CHAHB), 4.53 (1H, d, J(H,H)= 12.3 Hz, CHAHB), 4.94-5.04 (2H, m,

CH2), 5.78-5.86 (1H, m, CH), 7.28-7.39 (5H, m, ArH); 13C NMR (125 MHz, CDCl3) = 17.2

(CH3), 31.4 (CH2), 33.0 (CH), 33.2 (CH2), 73.2 (CH2), 76.0 (CH2), 114.5 (CH2), 127.6 (CH),

127.7 (CH), 128.5 (CH), 139.0 (C), 139.3 (CH); IR (thin film) (cm-1) = 3065, 3030, 2928,

2854, 1641, 1496, 1453, 1363, 1099, 910, 735, 697; MS (ESI) 332 (100), 227 (25) [M+Na]+;

HRMS: m/z calcd for C14H20Na1O1 [M+Na]+: 227.1406; found: 227.1402.

(4R)-5-(Benzyloxy)-4-methylpentanal 12

BnO O

12

Ozone was bubbled through a solution of (((2R)-2-methylhex-5-en-1-ol)oxy)methyl)benzene

11 (3.5 g, 17.1 mmol, 1.0 eq) in dry DCM (50 mL) at -78 C until a pale blue colour appeared

(approx. 45 min). Oxygen was bubbled through the reaction until the blue colour disappeared.

Triphenylphosphine (4.9 g, 18.8 mmol, 1.1 eq) was added and the reaction was stirred at -78

C for 1 h, then warmed to r.t. and stirred for 18 h. The solvent was removed in vacuo.

Purification by column chromatography using silica gel (EtOAc/Pet. ether 1:19) gave (4R)-5-

(benzyloxy)-4-methylpentanal 12 (1.93 g, 55%) as a colourless oil; 1H NMR (500 MHz,

CDCl3) = 0.95 (3H, d, J(H,H)= 6.5 Hz, CH3), 1.47-1.55 (1H, m, CHAHB), 1.77-1.87 (2H,

m, CHAHB, CH), 2.05-2.53 (2H, m, CH2), 3.29-3.34 (2H, m, CH2), 4.50 (2H, s, CH2), 7.27-

7.37 (5H, m, ArH), 9.77 (1H, t, J(H,H)= 1.7 Hz, CHO); 13C NMR (125 MHz, CDCl3) =

17.1 (CH3), 26.1 (CH2), 33.3 (CH), 41.8 (CH2), 73.2 (CH2), 75.5 (CH2), 127.7 (CH), 127.8

(CH), 128.6 (CH), 138.7 (C), 203.0 (CO).

5-((4-Methoxyphenyl)methoxy)pentan-1-ol 25aHO OPMB

25a

Using a modification of the reported5 procedure, 1,5-pentanediol 24a (31.4 mL, 300 mmol,

3.0 eq) was added to a suspension of sodium hydride (60% in oil, 4.2 g, 105 mmol, 1.05 eq)

in dry THF (400 mL) at 0 C under argon. The reaction mixture was warmed to r.t. and

stirred for 1 h. 4-Methoxybenzyl chloride (13.6 mL, 100 mmol, 1.0 eq) was added, followed

by tetrabutylammonium iodide (14.8 g, 40 mmol, 0.4 eq). The reaction mixture was heated to

60 C and stirred for 18 h. The reaction mixture was cooled to r.t. and quenched with water

(400 mL). The organic layer was separated and the aqueous layer was re-extracted with

diethyl ether (2 x 200 mL), dried over anhydrous Na2SO4 and the solvent was removed in

vacuo. Purification by column chromatography using silica gel (EtOAc/Pet. ether 1:1) gave

5-((4-methoxyphenyl)methoxy)pentan-1-ol 25a (19.1 g, 85%) as a colourless oil; 1H NMR

(400 MHz, CDCl3) = 1.41-1.48 (3H, m, CH2, OH), 1.56-1.68 (4H, m, CH2), 3.45 (2H, t,

J(H,H)= 6.5 Hz, CH2), 3.65 (2H, t, J(H,H)= 6.6 Hz, CH2), 3.81 (3H, s, CH3), 4.44 (2H, s,

CH2), 6.87-6.90 (2H, m, ArH), 7.25-7.28 (2H, m, ArH); 13C NMR (100 MHz, CDCl3) =

22.7 (CH2), 29.7 (CH2), 32.7 (CH2), 55.5 (CH3), 63.1 (CH2), 70.2 (CH2), 72.8 (CH2), 114.0

(CH), 129.5 (CH), 130.9 (C), 159.3 (C); IR (thin film) (cm-1) = 3404, 2937, 2862, 1613,

1586, 1513, 1464, 1362, 1302, 1248, 1174, 1096, 1035, 820; MS (ESI) 247 (100) [M + Na]+,

121 (30); HRMS: m/z calcd for C13H20Na1O2 [M+Na]+: 247.1305; found: 247.1297.

6-((4-Methoxyphenyl)methoxy)hexan-1-ol 25b

HOOPMB

25b

Following the same procedure as 25a, 1,6-hexanediol 24b (5 g, 42 mmol, 1.0 eq) was reacted

to give 6-((4-methoxyphenyl)methoxy)hexan-1-ol 25b (5.5 g, 55%) as a colourless oil; 1H

NMR (400 MHz, CDCl3) = 1.35-1.44 (4H, m, CH2), 1.46 (1H, bs, OH), 1.54-1.65 (4H, m,

CH2), 3.45 (2H, t, J(H,H)= 6.6 Hz, CH2), 3.63 (2H, t, J(H,H)= 6.6 Hz, CH2), 3.81 (3H, s,

CH3), 4.44 (2H, s, CH2), 6.87-6.90 (2H, m, ArH), 7.25-7.29 (2H, m, ArH); 13C NMR (100

MHz, CDCl3) = 25.8 (CH2), 26.2 (CH2), 29.9 (CH2), 32.9 (CH2), 55.5 (CH3), 70.2 (CH2),

72.7 (CH2), 113.9 (CH), 129.4 (CH), 130.9 (C), 159.3 (C); IR (thin film) (cm-1) = 3397,

2935, 2859, 1710, 1612, 1586, 1514, 1464, 1249, 1173, 1095, 1035, 822, 738; MS (ESI) 261

(100) [M+Na]+; HRMS: m/z calcd for C14H22Na1O2 [M+Na]+: 261.1461; found: 261.1455.

5-((4-Methoxyphenyl)methoxy)pentanal 49aO OPMB

49a

A solution of DMSO (13.2 mL, 186 mmol, 3.0 eq) in dry DCM (40 mL) was added to a

solution of oxalyl chloride (11 mL, 130 mmol, 2.1 eq) in dry DCM (360 mL) at -78 C under

argon and stirred for 30 min. A solution of 5-((4-methoxyphenyl)methoxy)pentan-1-ol 25a

(13.9 g, 62 mmol, 1.0 eq) in dry DCM (100 mL) was slowly added and the reaction mixture

was stirred at -78 C for 1.5 h. Triethylamine (43 mL, 310 mmol, 5.0 eq) was added and the

reaction mixture was warmed to 0 C and stirred for 1 h. Water (500 mL) was added and the

organic layer was separated. The aqueous layer was extracted with DCM (300 mL). The

combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4

and the solvent was removed in vacuo to give 5-((4-methoxyphenyl)methoxy)pentanal 49a

(13.8 g, 100%) as a yellow oil, which was used without further purification; 1H NMR (400

MHz, CDCl3) = 1.56-1.78 (4H, m, CH2), 2.46 (2H, dt, J(H,H)= 7.3, 1.7 Hz, CH2), 3.46 (2H,

t, J(H,H)= 6.0 Hz, CH2), 3.81 (3H, s, CH3), 4.43 (2H, s, CH2), 6.87-6.94 (2H, m, ArH), 7.25-

7.27 (2H, m, ArH), 9.77 (1H, t, J(H,H)= 1.7 Hz, CHO); 13C NMR (100 MHz, CDCl3) =

19.2 (CH2), 29.3 (CH2), 43.8 (CH2), 55.5 (CH3), 69.6 (CH2), 72.8 (CH2), 114.0 (CH), 129.5

(CH), 130.7 (C), 159.3 (C), 202.8 (CHO).

6-((4-Methoxyphenyl)methoxy)hexanal 49b

OOPMB

49b

DMP (10.7 g, 25.2 mmol, 1.2 eq) was added to a solution of 6-((4-

methoxyphenyl)methoxy)hexan-1-ol 25b (5.0 g, 21.0 mmol, 1.0 eq) in DCM (200 mL) at r.t.

The reaction mixture was stirred at r.t. for 18 h. The reaction mixture was diluted with diethyl

ether (100 mL) and sat. NaHCO3 solution (100 mL). Sodium thiosulfate (12 g) was added

and the reaction mixture was stirred vigorously for 30 min. The organic layer was separated

and the aqueous layer was extracted with diethyl ether (100 mL). The combined organic

layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and the solvent was

removed in vacuo to give 6-((4-methoxyphenyl)methoxy)hexanal 49b (5.0 g, 100%) as a

yellow oil, which was used without further purification; 1H NMR (400 MHz, CDCl3) =

1.38-1.46 (2H, m, CH2), 1.56-1.69 (4H, m, CH2), 2.44 (2H, dt, J(H,H)= 7.4, 1.8 Hz, CH2),

3.45 (2H, t, J(H,H)= 6.5 Hz, CH2), 3.81 (3H, s, CH3), 4.43 (2H, s, CH2), 6.87-6.90 (2H, m,

ArH), 7.25-7.28 (2H, m, ArH), 9.77 (1H, t, J(H,H)= 1.8 Hz, CHO); 13C NMR (100 MHz,

CDCl3) = 22.1 (CH2), 26.1 (CH2), 29.7 (CH2), 44.1 (CH2), 55.5 (CH3), 69.9 (CH2), 72.8

(CH2), 114.0 (CH), 129.5 (CH), 130.8 (C), 159.3 (C), 202.9 (CHO).

7-((4-Methoxyphenyl)methoxy)hept-1-yn-3-ol 26aHO OPMB

26a

Ethynylmagnesium bromide solution (0.5 M in THF, 150 mL, 74.4 mmol, 1.2 eq) was added

to a solution of 5-((4-methoxyphenyl)methoxy)pentanal 49a (13.8 g, 62.0 mmol, 1.0 eq) in

dry THF (200 mL) at 0 C under argon. The reaction mixture was stirred at 0 C for 2 h, then

allowed to warm to r.t. and stirred for a further 16 h. The reaction mixture was quenched with

sat. NH4Cl solution (300 mL). The organic layer was separated and the aqueous layer was re-

extracted with diethyl ether (2 x 200 mL). The combined organic layers were washed with

brine (300 mL), dried over anhydrous Na2SO4 and the solvent was removed in vacuo.

Purification by column chromatography using silica gel (EtOAc/Pet. ether 1:4) gave 7-((4-

methoxyphenyl)methoxy)hept-1-yn-3-ol 26a (10.9 g, 71%) as a pale yellow oil; 1H NMR

(500 MHz, CDCl3) = 1.52-1.79 (8H, m, CH2), 2.47 (1H, d, J(H,H)= 2.1 Hz, CH), 3.47 (2H,

t, J(H,H)= 6.5 Hz, CH2), 3.81 (3H, s, CH3), 4.38 (1H, td, J(H,H)= 6.5, 2.1 Hz, CH), 4.44 (2H,

s, CH2), 6.87-6.90 (2H, m, ArH), 7.26-7.28 (2H, m, ArH); 13C NMR (125 MHz, CDCl3) =

22.0 (CH2), 29.5 (CH2), 37.5 (CH2), 55.5 (CH3), 62.4 (CH), 70.0 (CH2), 72.8 (CH2), 73.2

(CH), 85.1 (C), 114.0 (CH), 129.5 (CH), 130.8 (C), 159.3 (C); IR (thin film) (cm-1) = 3406,

3290, 2941, 2863, 1612, 1586, 1513, 1464, 1303, 1248, 1174, 1094, 1034, 821, 638; MS

(ESI) 271 (100) [M+Na]+; HRMS: m/z calcd for C15H20Na1O3 [M+Na]+: 271.1305; found:

271.1299.

8-((4-Methoxyphenyl)methoxy)oct-1-yn-3-ol 26b

HOOPMB

26b

Following the same procedure as 26a, 6-((4-methoxyphenyl)methoxy)hexanal 49b (5.0 g,

21.0 mmol, 1.0 eq) was reacted to give 8-((4-methoxyphenyl)methoxy)oct-1-yn-3-ol 26b (4.2

g, 77%) as a pale yellow oil; 1H NMR (500 MHz, CDCl3) = 1.38-1.52 (4H, m, CH2), 1.60-

1.66 (2H, m, CH2), 1.68-1.77 (2H, m, CH2), 1.79 (1H, bs, OH), 2.47 (1H, d, J(H,H)= 2.1 Hz,

CH), 3.45 (2H, t, J(H,H)= 6.6 Hz, CH2), 3.81 (3H, s, CH3), 4.37 (1H, td, J(H,H)= 6.6, 2.1 Hz,

CH), 43.44 (2H, s, CH2), 6.87-6.91 (2H, m, ArH), 7.26-7.28 (2H, m, ArH); 13C NMR (125

MHz, CDCl3) = 25.0 (CH2), 26.1 (CH2), 29.8 (CH2), 37.8 (CH2), 55.5 (CH3), 62.4 (CH),

70.1 (CH2), 72.7 (CH2), 73.1 (CH), 85.1 (C), 114.0 (CH), 129.5 (CH), 130.9 (C), 159.3 (C);

IR (thin film) (cm-1) = 3398, 3289, 2939, 2861, 2092, 1681, 1612, 1513, 1464, 1303, 1249,

1174, 1090, 1034, 821, 643; MS (ESI) 285 (100) [M+Na]+, 121 (30); HRMS: m/z calcd for

C16H22Na1O3 [M+Na]+: 285.1461; found: 285.1454.

7-((4-Methoxyphenyl)methoxy)hept-1-yn-3-one 27aO OPMB

27a

DMP (20.5 g, 48.3 mmol, 1.2 eq) was added to a solution of 7-((4-

methoxyphenyl)methoxy)hept-1-yn-3-ol 26a (10.0 g, 40.3 mmol, 1.0 eq) in DCM (200 mL)

at r.t. and stirred at r.t. for 2 h. The reaction mixture was diluted with diethyl ether (200 mL)

and sat. NaHCO3 solution (200 mL). Sodium thiosulfate (30 g) was added and the reaction

mixture was stirred vigorously for 30 min. The organic layer was separated and the aqueous

layer was extracted with diethyl ether (200 mL). The combined organic layers were washed

with brine (500 mL), dried over anhydrous Na2SO4 and the solvent was removed in vacuo to

give 7-((4-methoxyphenyl)methoxy)hept-1-yn-3-one 27a (9.1 g, 85%) as a yellow oil, which

was used without further purification; 1H NMR (500 MHz, CDCl3) = 1.62-1.68 (2H, m,

CH2), 1.76-1.82 (2H, m, CH2), 2.63 (2H, t, J(H,H)= 7.4 Hz, CH2), 3.21 (1H, s, CH), 3.47

(2H, t, J(H,H)= 6.3 Hz, CH2), 3.82 (3H, s, CH3), 4.44 (2H, s, CH2), 6.89-6.91 (2H, m, ArH),

7.27-7.28 (2H, m, ArH); 13C NMR (125 MHz, CDCl3) = 20.8 (CH2), 29.1 (CH2), 45.3

(CH2), 55.5 (CH3), 69.6 (CH2), 72.8 (CH2), 78.6 (C), 81.6 (C), 114.0 (CH), 129.5 (CH), 130.7

(C), 159.3 (C), 187.4 (CO); IR (thin film) (cm-1) = 3261, 2938, 2862, 2092, 1683, 1613,

1513, 1465, 1303, 1248, 1174, 1099, 1035, 821, 737; MS (ESI) 269 (100) [M+Na]+, 259

(20), 121 (25); HRMS: m/z calcd for C15H18Na1O3 [M+Na]+: 269.1148; found: 269.1141.

8-((4-Methoxyphenyl)methoxy)oct-1-yn-3-one 27b

OOPMB

27b

Following the same procedure as 27a, 8-((4-methoxyphenyl)methoxy)oct-1-yn-3-ol (2.09 g,

8.0 mmol, 1.0 eq) was reacted to give 8-((4-methoxyphenyl)methoxy)oct-1-yn-3-one 27b

(1.48 g, 71%) as a yellow oil; 1H NMR (500 MHz, CDCl3) = 1.37-1.45 (2H, m, CH2), 1.58-

1.74 (4H, m, CH2), 2.60 (1H, d, J(H,H)= 7.5 Hz, CH2), 3.20 (1H, s, CH), 3.45 (2H, t,

J(H,H)= 6.5 Hz, CH2), 3.81 (3H, s, CH3), 4.43 (2H, s, CH2), 6.87-6.90 (2H, m, ArH), 7.24-

7.27 (2H, m, ArH); 13C NMR (125 MHz, CDCl3) = 23.8 (CH2), 25.8 (CH2), 29.7 (CH2),

45.6 (CH2), 55.5 (CH3), 69.9 (CH2), 72.8 (CH2), 78.6 (CH), 81.6 (C), 114.0 (CH), 129.5

(CH), 130.9 (C), 159.4 (C), 187.6 (CO); IR (thin film) (cm-1) = 3259, 2938, 2862, 2092,

1683, 1612, 1513, 1248, 1100, 1034, 821; MS (ESI) 283 (100) [M+Na]+; HRMS: m/z calcd

for C16H20Na1O3 [M+Na]+: 283.1305; found: 283.1299.

1-(((5,5-Difluorohept-6-yn-1-yl)oxy)methyl)-4-methoxybenzene 28aOPMBF

F

28a

DAST (10.6 mL, 80 mmol, 4.0 eq) was added to a Teflon flask containing 7-((4-

methoxyphenyl)methoxy)hept-1-yn-3-one 27a (4.9 g, 20.0 mmol, 1.0 eq) under argon and

heated at 50 C for 18 h. The reaction mixture was cooled to r.t. and poured onto sat.

NaHCO3 solution (200 mL). The reaction mixture was extracted with DCM (2 x 200 mL).

The combined organic layers were washed with brine (400 mL), dried over anhydrous

Na2SO4 and the solvent was removed in vacuo. Purification by column chromatography using

silica gel (EtOAc/Pet. ether 1:19) gave 1-(((5,5-difluorohept-6-yn-1-yl)oxy)methyl)-4-

methoxybenzene 28a (3.25 g, 61%) as an orange oil; 1H NMR (500 MHz, CDCl3) = 1.62-

1.78 (4H, m, CH2), 2.02-2.11 (2H, m, CH2), 2.76 (1H, t, J(H,F)= 4.9 Hz, CH), 3.47 (2H, t,

J(H,H)= 5.5 Hz, CH2), 3.82 (3H, s, CH3), 4.45 (2H, s, CH2), 6.88-6.90 (2H, m, ArH), 7.26-

7.28 (2H, m, ArH); 13C NMR (125 MHz, CDCl3) = 19.8 (CH2, t, J(C,F)= 3.7 Hz), 29.2

(CH2), 39.0 (CH2, t, J(C,F)= 25.6 Hz), 55.5 (CH3), 69.6 (CH2), 72.8 (CH2), 75.4 (CH, t,

J(C,F)= 6.8 Hz), 76.8 (C, t, J(C,F)= 41.3 Hz), 114.0 (CH), 114.5 (CF2, t, J(C,F)= 232.9 Hz),

129.5 (CH), 130.7 (C), 159.4 (C); 19F{1H} NMR (282 MHz, CDCl3) = -84.0 (2F, s, CF2); 19F NMR (376 MHz, CDCl3) = -84.0 (2F, td, J(H,F)= 14.9, 4.8 Hz, CF2); IR (thin film)

(cm-1) = 3301, 2939, 2861, 2133, 1613, 1514, 1465, 1303, 1249, 1175, 1101, 1036, 821, 685;

MS (ESI) 291 (100) [M+Na]+, 271 (20), 121 (25); HRMS: m/z calcd for C15H18F2Na1O2

[M+Na]+: 291.1167; found: 291.1161.

1-(((6,6-Difluorooct-7-yn-1-yl)oxy)methyl)-4-methoxybenzene 28b

OPMBFF

28b

Following the same procedure as 28a, 8-((4-methoxyphenyl)methoxy)oct-1-yn-3-one (3.51 g,

13.5 mmol, 1.0 eq) was reacted to give 1-(((6,6-difluorooct-7-yn-1-yl)oxy)methyl)-4-

methoxybenzene 28b (1.93 g, 51%) as an orange oil; 1H NMR (500 MHz, CDCl3) = 1.41-

1.67 (6H, m, CH2), 1.99-2.10 (2H, m, CH2), 2.75 (1H, t, J(H,F)= 4.9 Hz, CH), 3.46 (2H, t,

J(H,H)= 6.4 Hz, CH2), 3.46 (3H, s, CH3), 4.44 (2H, s, CH2), 6.87-6.91 (2H, m, ArH), 7.26-

7.29 (2H, m, ArH); 13C NMR (125 MHz, CDCl3) = 22.7 (CH2, t, J(C,F)= 3.4 Hz), 25.8

(CH2), 29.7 (CH2), 39.2 (CH2, t, J(C,F)= 25.6 Hz), 55.5 (CH3), 69.9 (CH2), 72.8 (CH2), 75.3

(CH, t, J(C,F)= 6.8 Hz), 76.8 (C, t, J(C,F)= 41.3 Hz), 114.0 (CH), 114.5 (CF2, t, J(C,F)=

233.0 Hz), 129.5 (CH), 130.8 (C), 159.3 (C); 19F{1H} NMR (376 MHz, CDCl3) = -84.5

(2F, s, CF2); 19F NMR (376 MHz, CDCl3) = -84.5 (2F, td, J(H,F)= 15.0, 4.9 Hz, CF2); IR

(thin film) (cm-1) = 3302, 2940, 2864, 2133, 1722, 1454, 1434, 1363, 1315, 1276, 1176,

1103, 1071, 1028, 738, 698.

(2R)-2-((Benzyloxy)methyl)-8,8-difluoro-13-(((4-methoxyphenyl)methoxy) tridec-6-yn-5-

ol 15

BnO1

23

45

6Me

OH

78

9

F F 10

11

12

13

OPMB

15

nBuLi (1.6 M in hexanes, 3.0 mL, 4.8 mmol, 1.0 eq) was added to a solution of (((6,6-

difluorooct-7-yn-1-yl)oxy)methyl)benzene 28b (1.21 g, 4.8 mmol, 1.0 eq) in dry THF (90

mL) at -78 C under argon and stirred for 30 min. A solution of (4R)-5-(benzyloxy)-4-

methylpentanal 12 (1.25 g, 5.3 mmol, 1.1 eq) in dry THF (10 mL) was added and the reaction

mixture was stirred at -78 C for 4 h, then allowed to warm to r.t. and stirred for 16 h. The

reaction mixture was quenched with sat. NH4Cl solution (100 mL) and diluted with diethyl

ether (50 mL). The organic layer was separated and the aqueous layer was extracted with

diethyl ether (50 mL). The combined organic layers were washed with brine (100 mL), dried

over anhydrous Na2SO4 and the solvent was removed in vacuo. Purification by column

chromatography using silica gel (EtOAc/Pet. ether 1:4) gave (2R)-13-(benzyloxy)-8,8-

difluoro-2-(((4-methoxyphenyl)methoxy)methyl)tridec-6-yn-5-ol 15 (1.44 g, 61%) as a

yellow oil, as a mixture of two diastereoisomers; [α]D +2.3 (c 1.02, CHCl3); 1H NMR (500

MHz, CDCl3) = 0.96 (3H, d, J(H,H)= 6.6 Hz, CH3), 0.97 (3H, d, J(H,H)= 6.6 Hz, CH3),

1.29-1.38 (1H, m, CH2-3), 1.44-1.51 (2H, m, CH2-10), 1.58-1.86 (11H, CH-2, CH2-3,4,11,12,

OH), 2.00-2.09 (2H, m, CH2-9), 3.30-3.36 (2H, m, CH2-1), 3.47 (2H, t, J(H,H)= 6.3 Hz, CH2-

13), 3.83 (3H, s, CH3), 4.39-4.45 (1H, m, CH-5), 4.45 (2H, s, CH2), 4.52 (2H, s, CH2), 6.89-

6.92 (2H, m, ArH), 7.29-7.38 (7H, m, ArH); 13C NMR (125 MHz, CDCl3) = 17.3 and 17.4

(CH3), 22.8 (CH2, t, J(C,F)= 2.9 Hz, C10), 25.8 (CH2, C11), 29.2 and 29.2 (CH2, C3), 29.6

(CH2, C12), 33.3 and 33.3 (CH, C2), 34.7 and 34.8 (CH2, C4), 39.2 (CH2, t, J(C,F)= 26.0 Hz,

C9), 55.5 (CH3), 62.3 and 62.4 (CH, C5), 69.9 (CH2, C13), 72.8 (CH2, Bn), 73.2 (CH2,

PMB), 75.8 (CH2, C1), 77.9-78.2 (C, m, C7), 88.1-88.3 (C, m, C6), 114.0 (CH), 115.0 (CF2,

d, J(C,F)= 231.8 Hz, C8), 127.7 (CH), 127.8 and 127.8 (CH), 129.5 (CH), 130.7 (C), 138.7

and 138.8 (C), 159.3 (C); 19F{1H} NMR (282 MHz, CDCl3) = -83.09 and -83.10 (2F, s,

CF2); 19F NMR (376 MHz, CDCl3) = -83.09 (2F, t, J(H,F)= 14.9 Hz, CF2) and -83.11 (2F, t,

J(H,F)= 14.9 Hz, CF2); IR (thin film) (cm-1) = 3401, 2936, 2864, 2250, 1613, 1513, 1455,

1248, 1174, 1097, 1033, 739, 699; MS (ESI) 511 (100) [M+Na]+, 491 (20); HRMS: m/z calcd

for C29H38F2Na1O4 [M+Na]+: 511.2630; found: 511.2621.

(2R)-2-((Benzyloxy)methyl)-8,8-difluoro-13-((4-methoxyphenyl)methoxy)tridec-6-yn-5-

one 29

BnO1

23

45

6Me

O

78

9

F F 10

11

12

13

OPMB

29

DMP (1.46 g, 3.4 mmol, 1.5 eq) was added to a solution of (2R)-13-(benzyloxy)-8,8-difluoro-

2-(((4-methoxyphenyl)methoxy)methyl)tridec-6-yn-5-ol 15 (1.4 g, 2.9 mmol, 1.0 eq) in DCM

(100 mL) at r.t. The reaction mixture was stirred at r.t. for 2 h, then diluted with diethyl ether

(50 mL) and sat. NaHCO3 solution (50 mL). Sodium thiosulfate (3 g) was added and the

reaction mixture was stirred vigorously for 30 min. The organic layer was separated and the

aqueous layer was extracted with diethyl ether (50 mL). The combined organic layers were

washed with brine (100 mL), dried over anhydrous Na2SO4 and the solvent was removed in

vacuo to give (2R)-13-(benzyloxy)-8,8-difluoro-13-(((4-methoxyphenyl)methoxy)methyl)-

tridec-6-yn-5-one 29 (1.26 g, 89%) as a yellow oil that was used without further purification;

[α]D +0.5 (c 1.02, CHCl3); 1H NMR (500 MHz, CDCl3) = 0.96 (3H, d, J(H,H)= 6.7 Hz,

CH3), 1.43-1.67 (7H, m, CH2-3,10,11,12), 1.78-1.94 (2H, m, CH-2, CH2-3), 2.04-2.14 (2H,

m, CH2-9), 2.63-2.74 (2H, m, CH2-4), 3.29-3.35 (2H, m, CH2-1), 3.46 (2H, t, J(H,H)= 6.4

Hz, CH2-13), 3.83 (3H, s, CH3), 4.45 (2H, s, CH2), 4.51 (2H, s, CH2), 6.89-6.91 (2H, m,

ArH), 7.27-7.39 (7H, m, ArH); 13C NMR (125 MHz, CDCl3) = 17.1 (CH3), 22.5 (CH2, t,

J(C,F)= 2.9 Hz, C10), 25.8 (CH2, C11), 27.6 (CH2, C3), 29.6 (CH2, C12), 33.0 (CH, C2),

38.9 (CH2, t, J(C,F)= 25.0 Hz, C9), 43.4 (CH2, C4), 55.5 (CH3), 69.8 (CH2, C13), 72.8 (CH2,

PMB), 73.2 (CH2, Bn), 75.4 (CH2, C1), 80.8 (C, t, J(C,F)= 42.1 Hz, C7), 82.6 (C, t, J(C,F)=

6.6 Hz, C7), 114.0 (CH), 114.6 (CF2, t, J(C,F)= 235.1 Hz, C8), 127.8 (CH), 127.8 (CH),

128.6 (CH), 129.4 (CH), 130.8 (C), 138.7 (C), 159.3 (C), 186.5 (CO, C5); 19F{1H} NMR

(470 MHz, CDCl3) = -85.5 (2F, s, CF2); 19F NMR (282 MHz, CDCl3) = -86.0 (2F, t,

J(H,F)= 15.2 Hz, CF2); MS (ESI) 509 (100) [M+Na]+, 489 (20); HRMS: m/z calcd for

C29H36F2Na1O4 [M+Na]+: 509.2474; found: 509.2463.

1-(((12R)-13-(Benzyloxy)-6,6,9,9-tetrafluoro-12-methyltridec-7-yn-1-yl)oxy)methyl)-4-

methoxybenzene 30

BnO13

1211

109

8Me

76

5

F F 4

3

2

1

OPMB

F F30

DAST (1.4 mL, 10.2 mmol, 4.0 eq) was added to a Teflon flask containing (2R)-13-

(benzyloxy)-8,8-difluoro-2-(((4-methoxyphenyl)methoxy)methyl)tridec-6-yn-5-one 29 (1.24

g, 2.5 mmol, 1.0 eq) under argon and heated at 50 C for 18 h. The reaction mixture was

cooled to r.t. and poured onto sat. NaHCO3 solution (200 mL). The reaction mixture was

extracted with DCM (2 x 150 mL). The combined organic layers were washed with brine

(200 mL), dried over anhydrous Na2SO4 and the solvent was removed in vacuo. Purification

by column chromatography using silica gel (EtOAc/Pet. ether 1:9) gave 1-(((12R)-13-

(benzyloxy)-6,6,9,9-tetrafluoro-12-methyltridec-7-yn-1-yl)oxy)methyl)-4-methoxybenzene

30 (0.90 g, 71%) as a yellow oil; [α]D +3.5 (c 1.05, CHCl3); 1H NMR (500 MHz, CDCl3) =

0.98 (3H, d, J(H,H)= 6.7 Hz, CH3), 1.42-1.67 (7H, m, CH2-2,3,4,11), 1.71-1.80 (1H, m, CH2-

11), 1.82-1.88 (1H, m, CH-12), 2.03-2.19 (4H, m, CH2-5,10), 3.29-3.36 (2H, m, CH2-13),

3.46 (2H, t, J(H,H)= 6.3 Hz, CH2-1), 3.82 (3H, s, CH3), 4.45 (2H, s, CH2), 4.52 (2H, s, CH2),

6.89-6.91 (2H, m, ArH), 7.27-7.38 (7H, m, ArH); 13C NMR (125 MHz, CDCl3) = 17.0

(CH3), 22.5 (CH2, t, J(C,F)= 3.2 Hz, C4), 25.8 (CH2, C3), 26.5 (CH2, t, J(C,F)= 3.3 Hz, C11),

29.6 (CH2, C2), 33.0 (CH, C12), 36.6 (CH2, t, J(C,F)= 25.1 Hz, C10), 38.9 (CH2, t, J(C,F)=

25.1 Hz, C5), 55.5 (CH3), 69.8 (CH2, C1), 72.8 (CH2, PMB), 73.3 (CH2, Bn), 75.3 (CH2,

C13), 78.8-79.6 (C, m, C7, C8), 114.0 (CH), 114.3 (CF2, t, J(C,F)= 235.3 Hz, C6), 114.5

(CF2, t, J(C,F)= 235.3 Hz, C9), 127.7 (CH), 127.8 (CH), 128.6 (CH), 129.4 (CH), 130.8 (C),

138.7 (C), 159.3 (C); 19F{1H} NMR (470 MHz, CDCl3) = -85.5 (2F, t, J(C,F)= 4.8 Hz,

CF2), -85.6 (2F, t, J(C,F)= 4.8 Hz, CF2); 19F NMR (470 MHz, CDCl3) = -85.4 (2F, tt,

J(H,F)= 15.2 Hz, J(F,F)= 4.8 Hz, CF2), -85.6 (2F, tt, J(H,F)= 15.1 Hz, J(F,F)= 4.8 Hz, CF2);

IR (thin film) (cm-1) = 2937, 2863, 2243, 1726, 1613, 1586, 1513, 1455, 1364, 1318, 1303,

1248, 1174, 1099, 1036, 822, 737, 699; MS (ESI) 531 (100) [M+Na]+, 511 (45); HRMS: m/z

calcd for C29H36F4Na1O3 [M+Na]+: 531.2493; found: 531.2483.

(12R)-12-((Benzyloxy)methyl)-6,6,9,9-tetrafluorotridec-7-yn-1-ol 31

BnO13

1211

109

8Me

76

5

F F 4

3

2

1

OH

F F31

DDQ (0.54 g, 2.4 mmol, 1.5 eq) was added to a solution of 1-(((12R)-13-(benzyloxy)-6,6,9,9-

tetrafluoro-12-methyltridec-7-yn-1-yl)oxy)methyl)-4-methoxybenzene 30 (0.8 g, 1.6 mmol,

1.0 eq) in DCM (50 mL) and water (0.5 mL) at r.t. and stirred for 2 h at r.t. The reaction

mixture was diluted with diethyl ether (100 mL) and sat. NaHCO3 solution (100 mL). The

organic layer was separated and the aqueous layer was extracted with diethyl ether (100 mL).

The combined organic layers were washed with water (150 mL), brine (150 mL), dried over

anhydrous Na2SO4 and the solvent was removed in vacuo. Purification by column

chromatography using silica gel (EtOAc/Pet. ether 1:4) gave (12R)-12-((benzyloxy)methyl)-

6,6,9,9-tetrafluorotridec-7-yn-1-ol 31 (0.48 g, 78%) as a colourless oil, with an inseparable

impurity; [α]D +5.4 (c 1.02, CHCl3); 1H NMR (500 MHz, CDCl3) = 0.97 (2H, d, J(H,H)=

6.6 Hz, CH3), 1.38-1.50 (8H, m, CH2-2,3,4,11, OH), 1.56-1.62 (1H, m, CH2-11), 1.81-1.88

(1H, m, CH2-12), 2.04-2.16 (4H, m, CH2-5,10), 3.28-3.36 (2H, m, CH2-13), 3.65 (2H, t,

J(H,H)= 6.5 Hz, CH2-1), 4.51 (2H, s, CH2), 7.27-7.38 (5H, m, ArH); 13C NMR (125 MHz,

CDCl3) = 17.0 (CH3), 22.5 (CH2, t, J(C,F)= 3.3 Hz, C4), 25.3 (CH2, C2), 26.5 (CH2, t,

J(C,F)= 3.3 Hz, C11), 32.5 (CH2, C3), 33.0 (CH, C12), 36.6 (CH2, t, J(C,F)= 25.0 Hz, C10),

38.9 (CH2, t, J(C,F)= 25.2 Hz, C5), 62.7 (CH2, C1), 73.3 (CH2, Bn), 75.3 (CH2, C13), 78.8-

79.5 (C, m, C7/C8), 114.3 (CH2, t, J(C,F)= 235.6 Hz, C6), 114.5 (CH2, t, J(C,F)= 235.6 Hz,

C9), 127.8 (CH), 127.8 (CH), 128.6 (CH), 138.6 (C); 19F{1H} NMR (470 MHz, CDCl3) = -

85.4 (2F, t, J(C,F)= 4.8 Hz, CF2), -85.6 (2F, t, J(C,F)= 4.8 Hz, CF2); 19F NMR (470 MHz,

CDCl3) = -85.4 (2F, tt, J(H,F)= 15.2 Hz, J(F,F)= 4.9 Hz, CF2), -85.6 (2F, tt, J(H,F)= 15.1

Hz, J(F,F)= 4.9 Hz, CF2); IR (thin film) (cm-1) = 3384, 2936, 2869, 2243, 1663, 1497,

1455, 1319, 1267, 1176, 1075, 1028, 739, 699; MS (ESI) 411 (100) [M+Na]+, 391 (45);

HRMS: m/z calcd for C21H28F4Na1O2 [M+Na]+: 411.1918; found: 411.1918.

(12R)-12-((Benzyloxy)methyl)-6,6,9,9-tetrafluorotridec-7-ynoic acid 32

BnO13

1211

109

8Me

76

5

F F 4

3

21 OH

F FO

32

BAIB (2.49 g, 7.7 mmol, 4.0 eq) and TEMPO (0.119 g, 0.8 mmol, 0.4 eq) were added to a

solution of (12R)-12-((benzyloxy)methyl)-6,6,9,9-tetrafluorotridec-7-yn-1-ol 31 (0.75 g, 1.9

mmol, 1.0 eq) in acetonitrile (6 mL) and water (6 mL) at r.t. and stirred for 7 h. The reaction

mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The

combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and

the solvent was removed in vacuo. Purification by column chromatography using silica gel

(EtOAc/Pet. ether 1:4, 1% AcOH) gave (12R)-12-((benzyloxy)methyl)-6,6,9,9-tetrafluoro-

tridec-7-ynoic acid 32 (0.45 g, 58%) as a yellow oil; [α]D +5.5 (c 1.07, CHCl3); 1H NMR

(500 MHz, CDCl3) = 0.96 (3H, d, J(H,H)= 6.8 Hz, CH3), 1.37-1.44 (1H, m, CH2-11), 1.59-

1.87 (5H, CH2-3,4,11), 1.81-1.87 (1H, m, CH-12), 2.03-2.18 (4H, m, CH2-5,10), 2.39 (2H, t,

J(H,H)= 7.2 Hz, CH2-2), 3.32 (1H, dd, J(H,H)= 7.2, 6.8 Hz, CHAHB-13), 3.35 (1H, dd,

J(H,H)= 7.2, 5.8 Hz, CHAHB-13), 4.53 (2H, s, CH2), 7.27-7.38 (5H, m, ArH); 13C NMR (125

MHz, CDCl3) = 16.9 (CH3), 22.2 (CH2, t, J(C,F)= 3.3 Hz, C4), 24.1 (CH2, C3), 26.5 (CH2,

t, J(C,F)= 3.3 Hz, C11), 33.0 (CH, C12), 33.5 (CH2, C2), 36.6 (CH2, t, J(C,F)= 25.3 Hz,

C10), 38.6 (CH2, t, J(C,F)= 25.0 Hz, C5), 73.2 (CH2, Bn), 75.3 (CH2, C13), 78.8-79.4 (C, m,

C7/C8), 114.2 (CH2, t, J(C,F)= 236.0 Hz, C6), 114.5 (CH2, t, J(C,F)= 236.0 Hz, C9), 127.9

(CH), 127.9 (CH), 128.6 (CH), 138.4 (C), 177.3 (CO, C1); 19F{1H} NMR (470 MHz, CDCl3)

= -85.3-(-85.3) (2F, m, CF2), -85.4-(-85.4) (2F, m, CF2); 19F NMR (470 MHz, CDCl3) = -

85.3-(-85.4) (4F, m, CF2); MS (ESI) 425 (100) [M+Na]+, 405 (40); HRMS: m/z calcd for

C21H26F4Na1O3 [M+Na]+: 425.1710; found: 425.1702.

Methyl (12R)-6,6,9,9-tetrafluoro-13-hydroxy-12-methyltridecanoate 33

HO13

1211

109

8

76

5

4

3

21 OMe

F F

F F

O33

A solution of (12R)-12-((benzyloxy)methyl)-6,6,9,9-tetrafluorotridec-7-ynoic acid 32 (0.43 g,

1.06 mmol, 1.0 eq) and palladium on carbon (10 wt% on carbon, 0.113 g, 0.11 mmol, 10

mol%) in methanol (20 mL) was stirred under a hydrogen atmosphere (1 atm) for 22 h. The

reaction mixture was filtered through celite and the celite was washed with methanol (20

mL). The methanol layers were combined and the solvent was removed in vacuo. Purification

by column chromatography using silica gel (EtOAc/Pet. ether 1:4, 1% AcOH) gave methyl

(12R)-6,6,9,9-tetrafluoro-13-hydroxy-12-methyltridecanoate 33 (0.227 g, 65%) as a white

solid; mp 40-42 C; [α]D +6.2 (c 1.11, CHCl3); 1H NMR (500 MHz, CDCl3) = 0.94 (3H, d,

J(H,H)= 6.4 Hz, CH3), 1.29-1.35 (1H, m, CH2-11), 1.49-1.71 (7H, m, CH-12, CH2-3,4,11,

OH), 1.81-1.96 (4H, m, CH2-5,10), 1.98-20.8 (4H, m, CH2-7,8), 2.35 (2H, t, J(H,H)= 7.4 Hz,

CH2-2), 3.50 (2H, d, J(H,H)= 5.7 Hz, CH2-13), 3.68 (3H, s, CH3); 13C NMR (125 MHz,

CDCl3) = 16.5 (CH3), 22.0 (CH2, t, J(C,F)= 4.5 Hz, C4), 24.7 (CH2, C3), 25.8 (CH2, t,

J(C,F)= 4.3 Hz, C11), 29.3 (CH2, t, J(C,F)= 25.8 Hz, C7/C8), 29.3 (CH2, t, J(C,F)= 25.8 Hz,

C7/C8), 33.9 (CH2, C2), 34.5 (CH2, t, J(C,F)= 25.2 Hz, C5/C10), 35.5 (CH, C12), 36.6 (CH2,

t, J(C,F)= 25.3 Hz, C5/C10), 51.8 (CH3), 68.0 (CH2, C13), 124.4 (CF2, t, J(C,F)= 241.5 Hz,

C6/C9), 124.7 (CF2, t, J(C,F)= 241.5 Hz, C6/C9), 174.0 (CO); 19F{1H} NMR (470 MHz,

CDCl3) = -99.8 (2F, s, CF2), -99.9 (2F, s, CF2); 19F NMR (470 MHz, CDCl3) = -99.8 (2F,

tt, J(H,F)= 16.1, 15.5 Hz, CF2), -99.9 (2F, tt, J(H,F)= 16.4, 16.1 Hz, CF2); IR (thin film)

(cm-1) = 3276, 2960, 2929, 1734, 1469, 1448, 1257, 1176, 1127, 1028, 980, 899, 799; MS

(ESI) 348 (100) [M+NH4]+, 331 (30); HRMS: m/z calcd for C15H30F4Na1O3 [M+NH4]+:

348.2156; found: 348.2157.

(12R)-6,6,9,9-Tetrafluoro-13-hydroxy-12-methyltridecanoic acid 34

HO13

1211

109

8

76

5

4

3

21 OH

F F

F F

O

34

Lithium hydroxide (22 mg, 0.93 mmol, 4.2 eq) was added to a solution of methyl (12R)-

6,6,9,9-tetrafluoro-13-hydroxy-12-methyltridecanoate 33 (73 mg, 0.22 mmol, 1.0 eq) in THF

(3 mL) and H2O (3 mL) at r.t. and stirred for 3 h. The reaction mixture was quenched with

sat. NH4Cl solution (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was

separated and washed with brine (20 mL), dried over anhydrous Na2SO4 and the solvent was

removed in vacuo to give (12R)-6,6,9,9-tetrafluoro-13-hydroxy-12-methyltridecanoic acid 34

(70 mg, 94%) as a white solid; mp 90-93 C; [α]D +12.6 (c 0.46, MeOH); 1H NMR (500

MHz, CDCl3) = 0.95 (3H, d, J(H,H)= 6.5 Hz, CH3), 1.25-1.37 (2H, m, CH2-11, OH), 1.52-

1.58 (2H, m, CH2-4), 1.62-1.73 (4H, m, CH-12, CH2-3,11), 1.82-1.94 (4H, m, CH2-5,10),

1.99-2.08 (4H, m, CH2-7,8), 2.40 (2H, t, J(H,H)= 7.2 Hz, CH2-2), 3.49-3.55 (2H, m, CH2-

13); 13C NMR (125 MHz, CDCl3) = 16.4 (CH3), 22.0 (CH2, t, J(C,F)= 4.1 Hz, C4), 24.5

(CH2, C3), 25.9 (CH2, t, J(C,F)= 4.7 Hz, C11), 29.0-29.5 (CH2, m, C7, C8), 33.5 (CH2, C2),

34.4 (CH2, t, J(C,F)= 25.2 Hz, C5/C10), 35.5 (CH, C12), 36.4 (CH2, t, J(C,F)= 25.2 Hz,

C5/C10), 68.1 (CH2, C13), 124.5 (CF2, t, J(C,F)= 240.0 Hz, C6/C9), 124.7 (CF2, t, J(C,F)=

241.4 Hz, C6/C9), 177.5 (CO); 19F{1H} NMR (470 MHz, CDCl3) = -99.85 (1F, s, CF2), -

78.86 (1F, s, CF2), -99.2 (2F, s, CF2); 19F NMR (470 MHz, CDCl3) = -98.8-(-98.9) (2F, m,

CF2), -99.2 (2F, tt, J(H,F)= 15.9, 14.5 Hz, CF2); MS (ESI) 315 (100) [M-H]¯, 255 (45);

HRMS: m/z calcd for C14H23F4O3 [M-H]¯: 315.1589; found: 315.1598.

(13R)-7,7,10,10-Tetrafluoro-13-methyl-1-oxacyclotetradecan-2-one 8

12

13

14

O1

2 3

45

678

9

10

11

O

FF F F

8

Triethylamine (0.48 mL, 3.41 mmol, 15.0 eq) and 2,4,6-trichlorobenzoyl chloride (0.33 mL,

2.28 mmol, 10.0 eq) were added to a solution of (12R)-6,6,9,9-tetrafluoro-13-hydroxy-12-

methyltridecanoic acid 34 (72 mg, 0.23 mmol, 1.0 eq) in dry THF (100 mL) at r.t. under

argon and stirred for 2.5 h. The reaction mixture was diluted with dry toluene (40 mL) and

added over 2 h using a syringe pump to a solution of 4-DMAP (0.56 g, 4.55 mmol, 20.0 eq)

in dry toluene (60 mL). The reaction mixture was stirred at r.t. for a further 1.5 h. The

reaction mixture was quenched with sat. NaHCO3 solution (60 mL) and diluted with DCM

(50 mL). The organic layer was separated and the aqueous layer was re-extracted with DCM

(50 mL). The combined organic layers were washed with brine (50 mL), dried over

anhydrous Na2SO4 and the solvent was removed in vacuo. Purification by column

chromatography using silica gel (EtOAc/Pet. ether 1:19) gave (13R)-7,7,10,10-tetrafluoro-13-

methyl-1-oxacyclotetradecan-2-one 8 (36.5 mg, 54%) as a white solid; mp 63-65 C; [α]D

+32.2 (c 0.58, CHCl3); 1H NMR (500 MHz, CDCl3) = 0.98 (3H, d, J(H,H)= 6.9 Hz, CH3),

1.26-2.06 (15H, m, CH-13, CH2-4,5,6,8,9,11,12), 2.36-2.51 (2H, m, CH2-3), 3.78 (1H, dd,

J(H,H)= 11.1, 9.2 Hz, CHAHB-14), 4.21 (1H, dd, J(H,H)= 11.1, 3.4 Hz, CHAHB-14); 13C

NMR (125 MHz, CDCl3) = 16.2 (CH3), 22.2 (CH2, t, J(C,F)= 5.8 Hz, C5), 24.4 (CH2, C4),

26.6 (CH2, t, J(C,F)= 5.0 Hz, C12), 28.1-28.7 (CH2, m, C7, C8), 31.6 (CH2, t, J(C,F)= 25.2

Hz, C11), 32.3 (CH, C13), 34.3 (CH2, t, J(C,F)= 25.3 Hz, C6), 35.4 (CH2, C2), 67.9 (CH2,

C14), 125.2 (CF2, t, J(C,F)= 240.9 Hz, C7), 125.5 (CF2, t, J(C,F)= 240.9 Hz, C10), 173.1

(CO, C2); 19F{1H} NMR (470 MHz, CDCl3) = -91.01 (1F, s, CF2), -91.04 (1F, s, CF2), -

91.09 (1F, d, J(F,F)= 246.9 Hz, CFAFB), -92.2 (1F, d, J(F,F)= 246.9 Hz, CFAFB); 19F NMR

(470 MHz, CDCl3) = -91.0-(-91.1) (2F, m, CF2), -91.09 (1F, dm, J(F,F)= 246.9 Hz,

CFAFB), -92.2 (1F, dm, J(F,F)= 246.9 Hz, CFAFB); MS (ASAP) 316 (60) [M+NH4]+, 298

(50) [M]+, 279 (100) [M-F]+, 261 (60), 241 (30); HRMS: m/z calcd for C14H26F4N1O2

[M+NH4]+: 316.1898; found: 316.1894.

2-((3R)-4-(Benzyloxy)-3-methylbutyl)oxirane 13

BnOO

13

mCPBA (3.45 g, 20 mmol, 2.0 eq) was added to a solution of (((2R)-2-methylhex-5-en-1-

ol)oxy)methyl)benzene 11 (2.04 g, 10 mmol, 1.0 eq) in DCM (100 mL) at r.t. and stirred for

18 h. The reaction mixture was diluted with DCM (100 mL) and washed with sodium sulfite

solution (10%, 200 mL), sat. NaHCO3 solution (200 mL), brine (200 mL), dried over

anhydrous Na2SO4 and the solvent was removed in vacuo. Purification by column

chromatography using silica gel (EtOAc/Pet. ether 1:19) gave 2-((3R)-4-(benzyloxy)-3-

methylbutyl)oxirane 13 (1.88 g, 55%) as a colourless oil as a 1:1 mixture of diastereoisomers;

[α]D +3.4 (c 0.99, CHCl3); 1H NMR (500 MHz, CDCl3) = 0.95 (3H, d, J(H,H)= 6.7 Hz,

CH3) and 0.96 (3H, d, J(H,H)= 6.8 Hz, CH3), 1.24-1.36 (1H, m, CH2), 1.49-1.69 (3H, m,

CH2), 1.78-1.86 (1H, m, CH), 2.47-2.49 (1H, m, CH2), 2.74-2.77 (1H, m, CH2), 2.90-2.93

(1H, m, CH), 3.27-3.35 (2H, m, CH2), 4.51 (2H, m, CH2), 7.27-7.37 (5H, m, ArH); 13C NMR

(125 MHz, CDCl3) = 17.2 and 17.2 (CH3), 29.9 and 30.0 (CH2), 30.1 and 30.2 (CH2), 33.5

and 33.5 (CH), 47.3 and 47.4 (CH2), 52.7 and 52.7 (CH), 73.2 and 73.2 (CH2), 75.8 (CH2),

127.7 (CH), 127.7 (CH), 128.5 (CH), 138.9 (C); IR (thin film) (cm-1) = 3032, 2925, 2855,

1496, 1454, 1364, 1260, 1206, 1099, 1029, 835, 737, 698; MS (ESI) 275 (30)

[M+MeOH+Na]+, 243 (100) [M+Na]+; HRMS: m/z calcd for C14H20Na1O2 [M+Na]+:

243.1356; found: 243.1350

(2R)-2-((Benzyloxy)methyl)-9,9-difluoro-13-((4-methoxyphenyl)methoxy)tridec-7-yn-5-

ol 16

BnO1

23

45

6Me

OH

78

910

11

12

13

OPMB

F F16

Following the same procedure reported for 15, 1-(((5,5-difluorohept-6-yn-1-yl)oxy)methyl)-

4-methoxybenzene 28a (3.6 g, 13.5 mmol, 1.0 eq) and 2-((3R)-4-(benzyloxy)-3-

methylbutyl)oxirane 13 (4.5 g, 20.3 mmol, 1.5 eq) gave (2R)-2-((benzyloxy)methyl)-9,9-

difluoro-13-((4-methoxyphenyl)methoxy)tridec-7-yn-5-ol 16 (4.0 g, 60%) as a yellow oil, as

a mixture of two diastereoisomers; [α]D +1.8 (c 1.04, CHCl3); 1H NMR (500 MHz, CDCl3)

= 0.94 (3H, d, J(H,H)= 6.7 Hz, CH3) and 0.95 (3H, d, J(H,H)= 6.7 Hz, CH3), 1.13-1.33 (1H,

m, CH2-3), 1.46-1.72 (7H, m, CH2-3,4,11,12), 1.76-1.85 (1H, m, CH-2), 1.91 (1H, bs, OH),

2.00-2.08 (2H, m, CH2-10), 2.38-2.62 (2H, m, CH2-6), 3.27-3.33 (2H, m, CH2-1), 3.45-3.47

(2H, m, CH2-13), 3.74-3.79 (1H, m, CH-5), 3.81 (3H, s, CH3), 4.44 (2H, s, CH2), 4.51 (2H, s,

CH2), 6.88-6.90 (2H, m, ArH), 7.26-7.37 (7H, m, ArH); 13C NMR (125 MHz, CDCl3) =

17.3 and 17.3 (CH3), 20.1 (CH2, C12), 27.4 and 27.6 (CH2, C6), 29.2 (CH2, C11), 29.7 and

29.7 (CH2, C3), 33.4 and 33.6 (CH, C2), 33.9 and 33.9 (CH2, C4), 39.3 (CH2, t, J(C,F)= 26.5

Hz, C10), 55.5 (CH3), 69.6 (CH2, C13), 69.9 and 70.1 (CH, C5), 72.8 (CH2, PMB), 73.2 and

73.3 (CH2, Bn), 75.8 and 75.9 (CH2, C1), 76.2 (C, t, J(C,F)= 41.0 Hz, C8) and 76.2 (C, t,

J(C,F)= 40.4 Hz, C8), 85.4 and 85.5 (C, C7), 114.0 (CH), 115.0 (CF2, t, J(C,F)= 231.6 Hz,

C9), 127.7 and 127.7 (CH), 127.8 and 127.8 (CH), 128.6 (CH), 129.5 (CH), 130.7 (C), 138.7

and 138.8 (C), 159.4 (C); 19F{1H} NMR (470 MHz, CDCl3) = -81.25 and -81.26 (2F, s,

CF2); MS (ESI) 511 (100) [M+Na]+; HRMS: m/z calcd for C29H38F2Na1O4 [M+Na]+:

511.2630; found: 511.2620.

(2R,7Z)-2-((Benzyloxy)methyl)-9,9-difluoro-13-((4-methoxyphenyl)methoxy)tridec-7-en-

1-ol 35

BnO1

23

45

6

7OH

8

9

10

11

12

13

OPMBF

F

35

A suspension of palladium (5% on barium sulfate, 600 mg) and quinoline (200 mg) in

pyridine (80 mL) was evacuated using high vacuum and flushed with hydrogen (1 atm). The

suspension was stirred under a hydrogen atmosphere for 5 minutes. A solution of (2R)-2-

((benzyloxy)methyl)-9,9-difluoro-13-((4-methoxyphenyl)methoxy)tridec-7-yn-5-ol 16 (2.0 g,

4.1 mmol, 1.0 eq) in pyridine (10 mL) was added and the reaction mixture was evacuated

using high vacuum and flushed with hydrogen (1 atm) three times. The reaction mixture was

stirred under hydrogen for 22 h. The reaction mixture was filtered through a plug of celite

and the celite was washed with ethyl acetate (200 mL). The washing were combined and the

solvent was removed in vacuo. Purification by column chromatography using silica gel

(EtOAc/Pet. ether 1:4) gave (2R,7Z)-2-((benzyloxy)methyl)-9,9-difluoro-13-((4-

methoxyphenyl)methoxy)tridec-7-en-1-ol 35 (1.64 g, 82%) as a colourless oil as a 1:1

mixture of two diastereoisomers; [α]D +0.8 (c 1.02, CHCl3); 1H NMR (500 MHz, CDCl3)

= 0.95 (3H, d, J(H,H)= 6.2 Hz, CH3) and 0.96 (3H, d, J(H,H)= 6.3 Hz, CH3), 1.16-1.34 (1H,

m, CH2-3), 1.40-1.69 (8H, m, CH2-3,4,11,12, OH), 1.77-1.82 (1H, m, CH-2), 1.90-2.00 (2H,

m, CH2-10), 2.38-2.50 (2H, m, CH2-6), 3.28-3.36 (2H, m, CH2-1), 3.47 (2H, t, J(H,H)= 6.2

Hz, CH2-13), 3.67-3.68 (1H, m, CH-5), 3.83 (3H, s, CH3), 4.45 (2H, s, CH2), 4.52 (2H, s,

CH2), 5.56-5.64 (1H, m, CH-8), 5.82-5.87 (1H, m, CH-7), 6.89-6.92 (2H, m, ArH), 7.27-7.38

(7H, m, ArH); 13C NMR (125 MHz, CDCl3) = 17.3 and 17.4 (CH3), 19.4 (CH2, t, J(C,F)=

3.9 Hz, C12), 29.6 (CH2, C11), 29.8 and 29.8 (CH2, C3), 33.5 and 33.7 (CH, C2), 34.7 and

34.8 (CH2, C4), 36.3 and 36.4 (CH2, C6), 38.4 (CH2, t, J(C,F)= 38.4 Hz, C10), 55.5 (CH3),

69.8 (CH2, C13), 71.7 and 71.9 (CH, C5), 72.8 (CH2, PMB), 73.2 and 73.2 (CH2, Bn), 75.8

and 76.0 (CH2, C1), 114.0 (CH), 122.7 (CF2, t, J(C,F)= 238.5 Hz, C9), 126.9 (CH, t, J(C,F)=

26.8 Hz, C8) and 127.0 (CH, t, J(C,F)= 26.8 Hz, C8), 127.7 and 127.7 (CH), 127.8 and 128.0

(CH), 128.5 (CH), 129.5 (CH), 130.7 (C), 134.1-134.2 (CH, m, C7), 138.8 and 138.9 (C),

159.3 (C); 19F{1H} NMR (470 MHz, CDCl3) = -90.2 and -90.2 (1F, d, J(F,F)= 248.0 Hz,

CFHAFB), -90.7 and -90.7 (1F, d, J(F,F)= 248.0 Hz, CFAFB); 19F NMR (470 MHz, CDCl3)

= -90.2 (1F, dm, J(F,F)= 248.0 Hz, CFAFB), -90.7 (1F, dm, J(F,F)= 248.0 Hz, CFAFB); MS

(ESI) 603 (35), 531 (65), 513 (100) [M+Na]+, 121 (30); HRMS: m/z calcd for C29H40F2Na1O4

[M+Na]+: 513.2787; found: 513.2785.

(2R,7Z)-2-((Benzyloxy)methyl)-9,9-difluoro-13-((4-methoxyphenyl)methoxy)tridec-7-en-

1-one 36

BnO1

23

45

6

7O

8

9

10

11

12

13

OPMBF

F

36

Following the same procedure reported for 29, (2R,7Z)-2-((benzyloxy)methyl)-9,9-difluoro-

13-((4-methoxyphenyl)methoxy)tridec-7-en-1-ol 35 (1.6 g, 3.3 mmol, 1.0 eq) gave (2R,7Z)-

2-((benzyloxy)methyl)-9,9-difluoro-13-((4-methoxyphenyl)methoxy)tridec-7-en-1-one 36

(0.90 g, 57%) as a colourless oil; [α]D -0.4 (c 1.01, CHCl3); 1H NMR (500 MHz, CDCl3) =

0.93 (3H, d, J(H,H)= 6.6 Hz, CH3), 1.43-1.84 (7H, m, CH-2, CH2-3,11,12), 1.86-1.98 (2H, m,

CH2-10), 2.20-2.63 (2H, m, CH2-6), 3.27-3.347 (2H, m, CH2-1), 3.42-3.47 (4H, m, CH2-

4,13), 3.81 (3H, s, CH3), 4.44 (2H, s, CH2), 4.49 (2H, s, CH2), 5.58-5.66 (1H, m, CH-8),

6.00-6.07 (1H, m, CH-7), 6.87-6.90 (2H, m, ArH), 7.25-7.37 (7H, m, ArH); 13C NMR (125

MHz, CDCl3) = 17.2 (CH3), 19.3 (CH2, t, J(C,F)= 4.1 Hz, C12), 27.8 (CH2, C3), 29.5 (CH2,

C11), 33.2 (CH2, C2), 38.2 (CH2, t, J(C,F)= 26.4 Hz, C10), 40.5 (CH2, C6), 41.6 (CH2, C4),

55.5 (CH3), 69.7 (CH2, C13), 72.8 (CH2, PMB), 73.2 (CH2, Bn), 75.6 (CH2, C1), 114.0 (CH),

122.6 (CF2, t, J(C,F)= 239.7 Hz, C9), 127.1 (CH2, t, J(C,F)= 26.4 Hz, C8), 127.7 (CH), 127.8

(CH), 128.5 (CH), 129.1 (CH2, t, J(C,F)= 5.4 Hz, C7), 129.4 (CH), 130.7 (C), 138.8 (C),

159.3 (CH), 207.7 (CO, C5); 19F{1H} NMR (470 MHz, CDCl3) = -91.9 (2F, s, CF2); 19F

NMR (470 MHz, CDCl3) = -91.8-(-91.9) (2F, m, CF2); MS (ESI) 511 (100) [M+Na]+, 121

(40); HRMS: m/z calcd for C29H38F2Na1O4 [M+Na]+: 511.2630; found: 511.2627.

1-((((6Z,12R)-13-(Benzyloxy)-5,5,9,9-tetrafluoro-12-methyltridec-6-en-1-yl)oxy)methyl)-

4-methoxybenzene 37

BnO13

1211

109

8

76

5

4

3

2

1

OPMBF

F

F F37

Following the same procedure reported for 30, (2R,7Z)-2-((benzyloxy)methyl)-9,9-difluoro-

13-((4-methoxyphenyl)methoxy)tridec-7-en-1-one 36 (1.0 g, 2.0 mmol, 1.0 eq) gave 1-

((((6Z,12R)-13-(benzyloxy)-5,5,9,9-tetrafluoro-12-methyltridec-6-en-1-yl)oxy)methyl)-4-

methoxybenzene 37 (0.29 g, 27%) as a yellow oil; [α]D -1.2 (c 1.53, CHCl3); 1H NMR (500

MHz, CDCl3) = 0.95 (3H, d, J(H,H)= 6.7 Hz, CH3), 1.30-1.70 (6H, m, CH2-2,3,11), 1.76-

1.98 (5H, CH-12, CH2-4,10), 2.82-3.03 (2H, m, CH2-8), 3.28-3.36 (2H, m, CH2-13), 3.45

(2H, t, J(H,H)= 6.2 Hz, CH2-1), 3.81 (3H, s, CH3), 4.44 (2H, s, CH2), 4.51 (2H, s, CH2), 5.54-

5.74 (1H, m, CH-6), 5.77-6.02 (1H, m, CH-7), 6.88-6.90 (2H, m, ArH), 7.26-7.38 (7H, m,

ArH); 13C NMR (125 MHz, CDCl3) = 17.1 (CH3), 19.3 (CH2, t, J(C,F)= 4.0 Hz, C3), 26.0

(CH2, t, J(C,F)= 4.1 Hz, C11), 29.6 (CH2, C2), 33.3 (CH2, C12), 34.1 (CH2, t, J(C,F)= 24.9

Hz, C10), 35.7 (CH2, t, J(C,F)= 26.1 Hz, C8), 38.3 (CH2, t, J(C,F)= 26.5 Hz, C4), 55.5 (CH3),

69.7 (CH2, C1), 72.8 (CH2, PMB), 73.2 (CH2, Bn), 75.6 (CH2, C13), 114.0 (CH), 122.5 (CF2,

t, J(C,F)= 239.4 Hz, C9), 124.2 (CF2, t, J(C,F)= 240.9 Hz, C5), 127.7 (CH), 127.8 (CH),

128.2-128.3 (CH, m, C7), 128.6 (CH, C6), 128.6 (CH), 129.4 (CH), 130.7 (C), 138.8 (C),

159.4 (C); 19F{1H} NMR (470 MHz, CDCl3) = -91.8 (2F, s, CF2), -98.5 (2F, s, CF2); 19F

NMR (470 MHz, CDCl3) = = -91.8 (2F, dt, J(H,F)= 15.6, 15.6 Hz, CF2), -98.5 (2F, tt,

J(H,F)= 16.5, 16.2 Hz, CF2); MS (ESI) 632 (15), 533 (50) [M+Na]+, 121 (100); HRMS: m/z

calcd for C29H38F4Na1O3 [M+Na]+: 533.2649; found: 533.2642.

(6Z,12R)-13-(Benzyloxy)-5,5,9,9-tetrafluoro-12-methyltridec-6-en-1-ol 38

BnO13

1211

109

8

76

5

4

3

2

1

OHF

F

F F38

Following the same procedure reported for 31, 1-((((6Z,12R)-13-(benzyloxy)-5,5,9,9-

tetrafluoro-12-methyltridec-6-en-1-yl)oxy)methyl)-4-methoxybenzene 37 (0.28 g, 0.5 mmol,

1.0 eq) gave (6Z,12R)-13-(benzyloxy)-5,5,9,9-tetrafluoro-12-methyltridec-6-en-1-ol 38 (0.15

g, 70%) as a colourless oil; [α]D -1.9 (c 1.14, CHCl3); 1H NMR (500 MHz, CDCl3) = 0.95

(3H, d, J(H,H)= 6.7 Hz, CH3), 13.0-1.44 (1H, m, CH2-11), 1.54-1.70 (5H, m, CH2-2,3,11),

1.73-2.00 (5H, CH-12, CH2-4,10), 2.82-3.02 (2H, m, CH2-8), 3.28-3.37 (2H, m, CH2-13),

4.50 (2H, s, CH2), 5.64-5.72 (1H, m, CH-6), 5.80-5.85 (1H, m, CH-7), 7.26-7.38 (5H, m,

ArH); 13C NMR (125 MHz, CDCl3) = 17.1 (CH3), 18.8 (CH2, t, J(C,F)= 4.1 Hz, C3), 26.1

(CH2, t, J(C,F)= 4.0 Hz, C11), 32.4 (CH2, C2), 33.4 (CH2, C12), 34.2 (CH2, t, J(C,F)= 25.0

Hz, C10), 35.7 (CH2, t, J(C,F)= 26.3 Hz, C8), 38.3 (CH2, t, J(C,F)= 26.5 Hz, C4), 62.6 (CH2,

C1), 73.3 (CH2, Bn), 75.6 (CH2, C13), 122.3 (CF2, t, J(C,F)= 240.1 Hz, C9), 124.2 (CF2, t,

J(C,F)= 242.1 Hz, C5), 127.7 (CH), 127.8 (CH), 128.2-128.5 (CH, m, C6 and C7), 128.6

(CH), 129.4 (CH), 138.8 (C); 19F{1H} NMR (470 MHz, CDCl3) = -91.8 (1F, s, CF2), -91.8

(1F, s, CF2), -98.6 (2F, s, CF2); 19F NMR (470 MHz, CDCl3) = = -91.8 (2F, dt, J(H,F)=

15.7, 15.4 Hz, CF2), -98.5 (2F, tt, J(H,F)= 16.6, 16.4 Hz, CF2); MS (ESI) 413 (100) [M+Na]+;

HRMS: m/z calcd for C21H30F4Na1O2 [M+Na]+: 413.2074; found: 413.2067.

(6Z,12R)-13-(Benzyloxy)-5,5,9,9-tetrafluoro-12-methyltridec-6-enoic acid 39

BnO13

1211

109

8

76

5

4

3

21 OH

FF

F F

O

39

Following the same procedure reported for 32, (6Z,12R)-13-(benzyloxy)-5,5,9,9-tetrafluoro-

12-methyltridec-6-en-1-ol 38 (0.15 g, 0.4 mmol, 1.0 eq) gave (6Z,12R)-13-(benzyloxy)-

5,5,9,9-tetrafluoro-12-methyltridec-6-enoic acid 39 (76 mg, 49%) as a colourless oil; [α]D -

0.5 (c 0.40, CHCl3); 1H NMR (500 MHz, CDCl3) = 0.95 (3H, d, J(H,H)= 6.7 Hz, CH3),

1.30-1.39 (1H, m, CHAHB-11), 1.63-1.70 (1H, m, CHAHB-11), 1.76-2.04 (7H, m, CH-12,

CH2-3,4,10), 2.44 (2H, t, J(H,H)= 7.3 Hz, CH2-2), 2.82-2.90 (2H, m, CH2-8), 3.29-3.34 (2H,

m, CH2-13), 4.52 (2H, s, CH2), 5.65-5.73 (1H, m, CH-6), 5.82-5.87 (1H, m, CH-7), 7.27-7.40

(5H, m, ArH); 13C NMR (125 MHz, CDCl3) = 17.1 (CH3), 17.6 (CH2, t, J(C,F)= 4.1 Hz,

C3), 26.1 (CH2, t, J(C,F)= 4.0 Hz, C11), 33.3 (CH, C12), 33.3 (CH2, C2), 34.2 (CH2, t,

J(C,F)= 24.8 Hz, C10), 35.7 (CH2, t, J(C,F)= 26.2 Hz, C8), 37.5 (CH2, t, J(C,F)= 26.8 Hz,

C4), 73.2 (CH2, Bn), 75.5 (CH2, C13), 122.2 (CF2, t, J(C,F)= 239.8 Hz, C5), 124.1 (CF2, t,

J(C,F)= 241.6 Hz, C9), 127.6 (CH), 127.8 (CH), 128.3 (CH, t, J(C,F)= 26.4 Hz, C6), 128.6

(CH), 128.6-128.8 (CH, m, C7), 138.7 (C), 178.9 (CO, C1); 19F{1H} NMR (470 MHz,

CDCl3) = -92.0 (2F, s, CF2-C5), -98.4 (2F, s, CF2-C9); 19F NMR (470 MHz, CDCl3) = -

90.1 (2F, dt, J(F,F)= 15.5, 15.4 Hz, CF2-C5), -98.4 (2F, tt, J(F,F)= 16.5, 16.5 Hz, CF2-C9);

MS (ESI) 560 (20), 473 (25), 427 (100) [M+Na]+, 126 (25); HRMS: m/z calcd for

C21H28F4Na1O3 [M+Na]+: 427.1867; found: 427.1861.

(12R)-5,5,9,9-Tetrafluoro-13-hydroxy-12-methyltridecanoate 40

HO13

1211

109

8

7

65

4

3

21 OMe

F F F F O40

Following the same procedure reported for 33, (6Z,12R)-13-(benzyloxy)-5,5,9,9-tetrafluoro-

12-methyltridec-6-enoic acid 39 (75 mg, 0.19 mmol, 1.0 eq) gave methyl (12R)-5,5,9,9-

tetrafluoro-13-hydroxy-12-methyltridecanoate 40 (36 g, 59%) as a white solid; [α]D +4.4 (c

0.25, CHCl3); 1H NMR (500 MHz, CDCl3) = 0.95 (3H, d, J(H,H)= 6.6 Hz, CH3), 1.25-1.34

(1H, m, CH2-11), 1.55 (1H, bs, OH), 1.60-1.72 (4H, m, CH-12, CH2-7,11), 1.77-1.95 (10H,

m, CH2-3,4,6,8,10), 2.39 (2H, t, J(H,H)= 6.9 Hz, CH2-2), 3.47-3.54 (2H, m, CH2-13), 3.69

(3H, s, CH3); 13C NMR (125 MHz, CDCl3) = 15.5-15.7 (CH2, m, C7), 16.6 (CH3), 18.0

(CH2, t, J(C,F)= 4.7 Hz, C3), 25.8 (CH2, t, J(C,F)= 4.2 Hz, C11), 33.5 (CH2, C2), 34.1 (CH2,

t, J(C,F)= 25.5 Hz, C10), 35.6 (CH2, C12), 35.8 (CH2, t, J(C,F)= 26.1 Hz, C8), 36.0 (CH2, t,

J(C,F)= 25.5 Hz, C4/C6), 36.1 (CH2, t, J(C,F)= 25.5 Hz, C4/C6), 51.9 (CH3), 68.0 (CH2,

C13), 124.8 (CF2, t, J(C,F)= 240.7 Hz, C5/C9), 125.2 (CF2, t, J(C,F)= 240.7 Hz, C5/C9),

173.7 (CO, C1); 19F{1H} NMR (470 MHz, CDCl3) = -98.5 (2F, s, CF2), -98.6 (2F, s, CF2); 19F NMR (470 MHz, CDCl3) = -98.5 (2F, tt, J(H,F)= 16.5, 16.5 Hz, CF2), -98.6 (2F, tt,

J(H,F)= 16.3, 16.3 Hz, CF2); MS (ESI) 353 (100) [M+Na]+, 316 (15); HRMS: m/z calcd for

C15H26F4Na1O3 [M+Na]+: 353.1710; found: 353.1699.

(13R)-6,6,10,10-Tetrafluoro-13-methyl-1-oxacyclotetradecan-2-one 9

12

13

14

O1

2 3

45

6

7

8

9

10

11

O

FF F

F

9

Lithium hydroxide (11 mg, 0.46 mmol, 4.2 eq) was added to a solution of methyl (12R)-

5,5,9,9-tetrafluoro-13-hydroxy-12-methyltridecanoate 40 (36 mg, 0.11 mmol, 1.0 eq) in THF

(1 mL) and H2O (1 mL) at r.t. and stirred for 3 h. The reaction mixture was quenched with

sat. NH4Cl solution (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was

separated and washed with brine (20 mL), dried over anhydrous Na2SO4 and the solvent was

removed in vacuo to give (12R)-6,6,9,9-tetrafluoro-13-hydroxy-12-methyltridecanoic acid 41

(24 mg, 70%) as a white solid that was immediately used for the next stage without further

purification.

Triethylamine (0.16 mL, 1.14 mmol, 15.0 eq) and 2,4,6-trichlorobenzoyl chloride (0.11 mL,

0.76 mmol, 10.0 eq) were added to a solution of (12R)-5,5,9,9-tetrafluoro-13-hydroxy-12-

methyltridecanoic acid 41 (24 mg, 0.08 mmol, 1.0 eq) in dry THF (5 mL) at r.t. under argon

and stirred for 2.5 h. The reaction mixture was diluted with dry toluene (20 mL) and added

over 2 h using a syringe pump to a solution of 4-DMAP (0.19 g, 1.52 mmol, 20.0 eq) in dry

toluene (30 mL). The reaction mixture was stirred at r.t. for 18 h. The reaction mixture was

quenched with sat. NaHCO3 solution (50 mL) and extracted with DCM (2 x 50 mL). The

combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4

and the solvent was removed in vacuo. Purification by column chromatography using silica

gel (EtOAc/Pet. ether 1:19) gave (13R)-6,6,10,10-tetrafluoro-13-methyl-1-oxacyclotetra-

decan-2-one 9 (12 mg, 52%) as a colourless oil; [α]D +9.2 (c 0.59, CHCl3); 1H NMR (500

MHz, CDCl3) = 1.00 (3H, d, J(H,H)= 7.0 Hz, CH3), 1.35-1.58 (4H, m, CH2-8,12), 1.77-

2.02 (11H, m, CH-13, CH2-4,5,7,9,11), 2.40-2.46 (1H, m, CH2-3), 2.49-2.54 (1H, m, CH2-3),

3.86 (1H, dd, J(H,H)= 11.3, 7.8 Hz, CH2-14), 4.20 (1H, dd, J(H,H)= 11.3, 3.4 Hz, CH2-14); 13C NMR (125 MHz, CDCl3) = 16.9 (CH3), 17.9 (CH2, tt, J(C,F)= 5.5, 5.5 Hz, C8), 19.0

(CH2, t, J(C,F)= 5.5 Hz, C4), 25.8 (CH2, t, J(C,F)= 5.3 Hz, C12), 30.9 (CH2, t, J(C,F)= 25.9

Hz, C11), 31.8 (CH, C13), 33.8 (CH2, t, J(C,F)= 26.0 Hz), 33.9 (CH2, t, J(C,F)= 25.9 Hz),

34.3 (CH2, t, J(C,F)= 25.9 Hz), 34.3 (CH2, C3), 67.2 (CH2, C14), 125.6 (CF2, t, J(C,F)=

240.4 Hz, C6), 126.1 (CF2, t, J(C,F)= 240.4 Hz, C10), 172.7 (CO, C2); 19F{1H} NMR (470

MHz, CDCl3) = -91.0 (2F, s, CF2), -91.2 (1F, d, J(F,F)= 248.5 Hz, CFAFB), -91.8 (1F, d,

J(F,F)= 248.5 Hz, CFAFB); 19F NMR (470 MHz, CDCl3) = -91.0 (2F, tt, J(H,F)= 14.7, 14.6

Hz, CF2), -91.2 (1F, dm, J(F,F)= 248.5 Hz, CFAFB), -91.8 (1F, dm, J(F,F)= 248.5 Hz,

CFAFB); HRMS: m/z calcd for C14H26F4N1O2 [M+NH4]+: 316.1894; found: 316.1888.

(5R)-6-(Benzyloxy)-5-methylhexan-1-ol 50

BnOOH

50

9-BBN dimer (3.66 g, 15 mmol, 1.0 eq) was added to a solution of (((2R)-2-methylhex-5-en-

1-ol)oxy)methyl)benzene 11 (3.06 g, 15 mmol, 1.0 eq) in dry THF (75 mL) under argon at 0

C. The reaction mixture was stirred at 0 C for 1 h, then warmed to r.t. and stirred for 22 h.

The reaction mixture was cooled to 0 C. Ethanol (10 mL), sodium hydroxide solution (2 N,

10 mL) and hydrogen peroxide (30%, 10 mL) were added. The reaction mixture was warmed

to r.t. and stirred for 3 h, and then the solvent was removed in vacuo. The reaction mixture

was diluted with ethyl acetate (200 mL) and washed with water (200 mL), brine (200 mL),

dried over anhydrous Na2SO4 and the solvent was removed in vacuo. Purification by column

chromatography using silica gel (EtOAc/Pet. ether 1:4) gave (5R)-6-(benzyloxy)-5-

methylhexan-1-ol 50 (1.99 g, 59%) as a colourless oil; [α]D +0.7 (c 1.05, CHCl3); 1H NMR

(500 MHz, CDCl3) = 0.94 (3H, d, J(H,H)= 6.7 Hz, CH3), 1.13-1.69 (7H, m, CH2, OH),

1.74-1.82 (1H, m, CH), 3.26 (1H, dd, J(H,H)= 9.1, 6.7 Hz, CHAHB), 3.33 (1H, dd, J(H,H)=

9.1, 6.1 Hz, CHAHB), 3.64 (2H, t, J(H,H)= 6.7 Hz, CH2), 4.50 (1H, d, J(H,H)= 12.8 Hz,

CHAHB), 4.52 (1H, dd, J(H,H)= 12.8 Hz, CHAHB), 7.27-7.37 (5H, m, ArH); 13C NMR (125

MHz, CDCl3) = 17.3 (CH3), 23.3 (CH2), 33.2 (CH2), 33.6 (CH2), 33.6 (CH), 63.2 (CH2),

73.2 (CH2), 76.1 (CH2), 127.7 (CH), 127.8 (CH), 128.5 (CH), 138.9 (C); MS (ESI) 277 (100)

[M+MeOH+Na]+, 245 (60) [M+Na]+; HRMS: m/z calcd for C14H22Na1O2 [M+Na]+:

245.1512; found: 245.1509.

(5R)-6-(Benzyloxy)-5-methylhexanal 14

BnOO

14

DMP (4.53 g, 10.7 mmol, 1.2 eq) was added to a solution of (5R)-6-(benzyloxy)-5-

methylhexan-1-ol 50 (1.98 g, 8.9 mmol, 1.0 eq) in DCM (100 mL) at r.t. The reaction

mixture was stirred at r.t. for 1 h, then diluted with diethyl ether (50 mL) and sat. NaHCO3

solution (100 mL). Sodium thiosulfate (7 g) was added and the reaction mixture was stirred

vigorously for 30 min. The organic layer was separated and the aqueous layer was extracted

with diethyl ether (50 mL). The combined organic layers were washed with brine (100 mL),

dried over anhydrous Na2SO4 and the solvent was removed in vacuo to give (5R)-6-

(benzyloxy)-5-methylhexanal 12 (2.0 g, 100%) as a yellow oil that was used without further

purification; 1H NMR (500 MHz, CDCl3) = 0.95 (3H, d, J(H,H)= 6.9 Hz, CH3), 1.14-1.22

(1H, m, CH2), 1.46-1.82 (4H, m, CH2, CH), 2.43 (2H, t, J(H,H)= 7.2 Hz, CH2), 3.28 (1H, dd,

J(H,H)= 9.0, 6.3 Hz, CHAHB), 3.32 (1H, dd, J(H,H)= 9.1, 6.3 Hz, CHAHB), 4.51 (2H, s,

CH2), 7.27-7.37 (5H, m, ArH), 9.77 (1H, t, J(H,H)= 1.6 Hz, CHO); 13C NMR (125 MHz,

CDCl3) = 17.2 (CH3), 19.7 (CH2), 33.4 (CH2), 33.6 (CH), 44.4 (CH2), 73.2 (CH2), 75.8

(CH2), 127.7 (CH), 127.8 (CH), 128.6 (CH), 138.9 (C), 203.0 (CHO).

1-((Hept-6-yn-1-yloxy)methyl)-4-methoxybenzene 43

PMBO

43

6-Heptyn-1-ol 42 (2.0 g, 17.8 mmol, 1.0 eq) was added to a suspension of sodium hydride

(60% in oil, 0.78 g, 19.6 mmol, 1.1 eq) in dry DMF (100 mL) at 0 C under argon. The

reaction mixture was stirred at 0 C for 30 min, then 4-methoxybenzyl chloride (2.7 mL, 19.6

mmol, 1.1 eq) was added. The reaction mixture was warmed to r.t. and stirred for 18 h. The

reaction mixture was quenched with water (200 mL) and diluted with ethyl acetate (250 mL).

The organic layer was separated and washed with water (3 x 250 mL), brine (250 mL), dried

over anhydrous Na2SO4 and the solvent was removed in vacuo. Purification by column

chromatography using silica gel (EtOAc/Pet. ether 1:9) gave 1-((hept-6-yn-1-yloxy)methyl)-

4-methoxybenzene 43 (3.58 g, 87%) as a colourless oil; 1H NMR (500 MHz, CDCl3) =

1.45-1.66 (6H, m, CH2), 1.95 (1H, t, J(H,H)= 2.6 Hz, CH), 2.20 (2H, dt, J(H,H)= 6.9, 2.6 Hz,

CH2), 3.46 (2H, t, J(H,H)= 6.5 Hz, CH2), 3.81 (3H, s, CH3), 4.44 (2H, s, CH2), 6.88-6.90

(2H, m, ArH), 7.26-7.28 (2H, m, ArH); 13C NMR (125 MHz, CDCl3) = 18.6 (CH2), 25.6

(CH2), 28.5 (CH2), 29.4 (CH2), 55.5 (CH3), 68.4 (CH), 70.1 (CH2), 72.8 (CH2), 84.8 (C),

114.0 (CH), 129.4 (CH), 130.9 (C), 159.3 (C); IR (thin film) (cm-1) = 3302, 2939, 2861,

2116, 1613, 1513, 1248, 1098, 1036, 821, 738, 637; MS (ESI) 287 (80) [M+MeOH+Na]+,

255 (100) [M+Na]+, 121 (45); HRMS: m/z calcd for C15H20Na1O2 [M+Na]+: 255.1356;

found: 255.1350.

(2R)-2-((Benzyloxy)methyl)-13-((4-methoxyphenyl)methoxy)tridec-7-yn-6-ol 17

BnO1

23

4

5

6 7

OH

8

9

10

11

12

13

OPMB

17

Following the same procedure reported for 15, 1-((hept-6-yn-1-yloxy)methyl)-4-

methoxybenzene 43 (1.88 g, 8.1 mmol, 1.0 eq) and (5R)-6-(benzyloxy)-5-methylhexanal 14

(1.96 g, 8.9 mmol, 1.1 eq) gave (2R)-2-((benzyloxy)methyl)-13-((4-

methoxyphenyl)methoxy)tridec-7-yn-6-ol 17 (2.92 g, 80%) as a colourless oil, as a mixture

of two diastereoisomers; [α]D +1.1 (c 1.07, CHCl3); 1H NMR (500 MHz, CDCl3) = 0.94

(3H, d, J(H,H)= 6.6 Hz, CH3), 1.14-1.16 (1H, m, CH2-3), 1.38-1.71 (12H, m, CH2-

3,4,5,10,11,12, OH), 1.76-1.82 (1H, m,CH-2), 2.21 (2H, t, J(H,H)= 7.1 Hz, CH2-9,

diastereomer A), 2.21 (2H, t, J(H,H)= 7.0 Hz, CH2-9, diastereomer B), 3.26 (1H, dd, J(H,H)=

8.9, 6.5 Hz, CHAHB-1), 3.31-3.35 (1H, m, CHAHB-1), 3.44 (2H, t, J(H,H)= 6.6 Hz, CH2-13),

3.81 (3H, s, CH3), 4.33-4.36 (1H, m, CH-6), 4.43 (2H, s, CH2), 4.49 (1H, d, J(H,H)= 12.5 Hz,

CHAHB), 4.52 (1H, d, J(H,H)= 12.5 Hz, CHAHB), 6.88-6.89 (2H, m, ArH), 7.26-7.37 (7H, m,

ArH); 13C NMR (125 MHz, CDCl3) = 17.3 and 17.3 (CH3), 18.9 (CH2, C9), 22.8 and 22.8

(CH2, C5), 25.7 (CH2, C10), 28.7 (CH2, C11), 29.5 (CH2, C12), 33.4 (CH2, C3), 33.6 (CH,

C2), 38.6 (CH2, C4), 55.5 (CH3), 62.9 and 62.9 (CH, C6), 70.1 (CH2, C13), 72.8 (CH2,

PMB), 73.2 (CH2, Bn), 76.1 and 76.1 (CH2, C1), 81.6 and 81.6 (C, C7), 85.5 and 85.6 (C,

C8), 114.0 (CH), 127.6 (CH), 127.7 (CH), 128.5 (CH), 129.5 (CH), 130.9 (C), 139.0 (C),

159.3 (C); IR (thin film) (cm-1) = 3413, 2935, 2862, 2212, 1613, 1513, 1454, 1248, 1097,

821, 737, 699; MS (ESI) 507 (50) [M+MeOH+Na]+, 475 (100) [M+Na]+; HRMS: m/z calcd

for C29H40Na1O4 [M+Na]+: 475.2819; found: 475.2809.

(2R)-2-((Benzyloxy)methyl)-13-((4-methoxyphenyl)methoxy)tridec-7-yn-6-one 44

BnO1

23

4

56

7

O

8

9

10

11

12

13

OPMB

44

Following the same procedure reported for 29, (2R)-2-((benzyloxy)methyl)-13-((4-

methoxyphenyl)methoxy)tridec-7-yn-6-ol 17 (2.8 g, 6.2 mmol, 1.0 eq) gave (2R)-2-

((benzyloxy)methyl)-13-((4-methoxyphenyl)methoxy)tridec-7-yn-6-one 44 (1.72 g, 61%) as

a colourless oil; [α]D +0.2 (c 1.03, CHCl3); 1H NMR (500 MHz, CDCl3) = 0.95 (3H, d,

J(H,H)= 6.7 Hz, CH3), 1.11-1.19 (1H, m, CH2-3), 1.43-1.81 (11H, m, CH-2, CH2-

3,4,10,11,12), 2.36 (2H, t, J(H,H)= 7.1 Hz, CH2-9), 2.47-2.57 (2H, m, CH2-5), 3.26 (1H, dd,

J(H,H)= 8.9, 6.4 Hz, CHAHB-1), 3.32 (1H, dd, J(H,H)= 9.1, 6.2 Hz, CHAHB-1), 3.45 (2H, t,

J(H,H)= 6.7 Hz, CH2-13), 3.81 (3H, s, CH3), 4.43 (2H, s, CH2), 4.49 (1H, d, J(H,H)= 12.6

Hz, CHAHB), 4.51 (1H, d, J(H,H)= 12.6 Hz, CHAHB), 6.87-6.89 (2H, m, ArH), 7.26-7.37

(7H, m, ArH); 13C NMR (125 MHz, CDCl3) = 17.2 (CH3), 19.1 (CH2, C9), 21.8 (CH2, C4),

25.8 (CH2, C11), 27.8 (CH2, C10), 29.4 (CH2, C12), 33.1 (CH2, C3), 33.6 (CH, C2), 46.0

(CH2, C5), 55.5 (CH3), 69.9 (CH2, C13), 72.8 (CH2, PMB), 73.2 (CH2, Bn), 75.9 (CH2, C1),

81.1 (C, C7), 94.2 (C, C8), 114.0 (CH), 127.7 (CH), 127.7 (CH), 128.5 (CH), 129.5 (CH),

130.8 (C), 138.9 (C), 159.3 (C), 188.6 (CO, C6); IR (thin film) (cm-1) = 2936, 2861, 2211,

1671, 1613, 1513, 1454, 1248, 1172, 1098, 1035, 822, 738, 699; MS (ESI) 505 (25)

[M+MeOH+Na]+, 487 (40), 473 (100) [M+Na]+; HRMS: m/z calcd for C29H38Na1O4

[M+Na]+: 473.2662; found: 473.2650.

1-((((12R)-13-(Benzyloxy)-8,8-difluoro-12-methyltridec-6-yn-1-ol)oxy)methyl)-4-

methoxybenzene 45

BnO1

23

4

56

78

9

10

11

12

13

OPMB

F F

45

Following the same procedure reported for 30, (2R)-2-((benzyloxy)methyl)-13-((4-

methoxyphenyl)methoxy)tridec-7-yn-6-one 44 (1.7 g, 3.8 mmol, 1.0 eq) gave 1-((((12R)-13-

(benzyloxy)-8,8-difluoro-12-methyltridec-6-yn-1-ol)oxy)methyl)-4-methoxybenzene 45 (1.01

g, 62%) as a yellow oil; [α]D -0.6 (c 1.09, CHCl3); 1H NMR (500 MHz, CDCl3) = 0.96

(3H, d, J(H,H)= 6.7 Hz, CH3), 1.15-1.22 (1H, m ,CH2-3), 1.45-1.67 (9H, CH2-3,4,10,11,12),

1.76-1.83 (1H, m, CH-2), 1.95-2.05 (2H, m, CH2-5), 2.25-2.30 (2H, m, CH2-9), 3.28 (1H, dd,

J(H,H)= 9.0, 6.3 Hz, CHAHB-1), 3.32 (1H, dd, J(H,H)= 9.0, 6.3 Hz, CHAHB-1), 3.45 (2H, t,

J(H,H)= 6.5 Hz, CH2-13), 3.81 (3H, s, CH3), 4.44 (2H, s, CH2), 4.51 (2H, s, CH2), 6.88-6.91

(2H, m, ArH), 7.26-7.38 (7H, m, ArH); 13C NMR (125 MHz, CDCl3) = 17.1 (CH3), 18.5

(CH2, C9), 20.6 (CH2, C4), 25.7 (CH2, C10), 27.9 (CH2, C11), 29.4 (CH2, C12), 33.1 (CH2,

C3), 33.5 (CH, C2), 39.9 (CH2, t, J(C,F)= 26.7 Hz, C5), 55.5 (CH3), 70.0 (CH2, C13), 72.8

(CH2, PMB), 73.2 (CH2, Bn), 74.3 (C, t, J(C,F)= 40.3 Hz, C7), 75.9 (CH2, C1), 88.6 (C, t,

J(C,F)= 6.4 Hz, C7), 114.0 (CH), 115.2 (CF2, t, J(C,F)= 230.1 Hz, C6), 127.7 (CH), 127.7

(CH), 128.5 (CH), 129.4 (CH), 130.8 (C), 138.9 (C), 159.3 (C); 19F{1H} NMR (376 MHz,

CDCl3) = -81.1 (1F, d, J(F,F)= 267.0 Hz, CFAFB), -81.9 (1F, d, J(F,F)= 267.0 Hz, CFAFB); 19F NMR (470 MHz, CDCl3) = -80.7 (1F, dm, J(F,F)= 267.3 Hz, CFAFB), -81.3 (1F, dm,

J(F,F)= 267.3 Hz, CFAFB); IR (thin film) (cm-1) = 2936, 2859, 2252, 1725, 1613, 1513,

1454, 1248, 1099, 821, 738, 699; MS (ESI) 527 (10) [M+MeOH+Na]+, 495 (100) [M+Na]+;

HRMS: m/z calcd for C29H38F2Na1O3 [M+Na]+: 495.2681; found: 495.2671.

(12R)-13-(Benzyloxy)-8,8-difluoro-12-methyltridec-6-yn-1-ol 46

BnO1

23

4

56

78

9

10

11

12

13

OH

F F

46

Following the same procedure reported for 31, 1-((((12R)-13-(benzyloxy)-8,8-difluoro-12-

methyltridec-6-yn-1-ol)oxy)methyl)-4-methoxybenzene 45 (0.5 g, 1.1 mmol, 1.0 eq) gave

(12R)-13-(benzyloxy)-8,8-difluoro-12-methyltridec-6-yn-1-ol 46 (0.33 g, 88%) as a

colourless oil; [α]D -0.5 (c 0.97, CHCl3); 1H NMR (500 MHz, CDCl3) = 0.95 (3H, d,

J(H,H)= 6.7 Hz, CH3), 1.16-1.22 (1H, m, CH2-3), 1.44-1.67 (10H, m, CH2-3,4,10,11,12,

OH), 1.75-1.83 (1H, m, CH-2), 1.95-2.04 (2H, m, CH2-5), 2.27-2.32 (2H, m, CH2-9), 3.27-

3.34 (2H, m, CH2-1), 3.65 (2H, t, J(H,H)= 6.5 Hz, CH2-13), 4.51 (2H, s, CH2), 7.27-7.37

(5H, m, ArH); 13C NMR (125 MHz, CDCl3) = 17.1 (CH3), 18.5 (CH2, C9), 20.7 (CH2, C4),

25.2 (CH2, C10), 27.8 (CH2, C11), 32.3 (CH2, C12), 33.2 (CH2, C3), 33.6 (CH, C2), 39.9

(CH2, t, J(C,F)= 26.7 Hz, C5), 62.8 (CH2, C13), 73.3 (CH2, Bn), 74.4 (C, t, J(C,F)= 40.2 Hz,

C7), 75.9 (CH2, C1), 88.5 (C, t, J(C,F)= 6.5 Hz, C8), 115.2 (CF2, t, J(C,F)= 230.7 Hz, C6),

127.7 (CH), 127.8 (CH), 128.6 (CH), 138.8 (C); 19F{1H} NMR (376 MHz, CDCl3) = -81.1

(1F, d, J(F,F)= 267.4 Hz, CFAFB), -81.9 (1F, d, J(F,F)= 267.4 Hz, CFAFB); 19F NMR (376

MHz, CDCl3) = -81.1 (1F, dm, J(F,F)= 267.1 Hz, CFAFB), -81.9 (1F, dm, J(F,F)= 267.1

Hz, CFAFB); IR (thin film) (cm-1) = 3396, 2936, 2863, 2252, 1454. 1319, 1157, 1097, 738,

699; MS (ESI) 407 (20) [M+MeOH+Na]+, 375 (100) [M+Na]+; HRMS: m/z calcd for

C21H30F2Na1O2 [M+Na]+: 375.2106; found: 375.2096.

(12R)-13-(Benzyloxy)-8,8-difluoro-12-methyltridec-6-ynoic acid 47

BnO1

23

4

56

78

9

10

11

1213 OH

F F

O47

Following the same procedure reported for 32, (12R)-13-(benzyloxy)-8,8-difluoro-12-

methyltridec-6-yn-1-ol 46 (280 mg, 0.8 mmol, 1.0 eq) gave (12R)-13-(benzyloxy)-8,8-

difluoro-12-methyltridec-6-ynoic acid 47 (0.14 g, 48%) as a yellow oil; [α]D +1.0 (c 0.64,

CHCl3) ; 1H NMR (500 MHz, CDCl3) = 0.94 (3H, d, J(H,H)= 6.7 Hz, CH3), 1.15-1.25 (1H,

m, CH2-3), 1.48-1.65 (5H, m, CH2-3,4,10), 1.73-1.82 (3H, m, CH-2, CH2-11), 1.95-2.04 (2H,

m, CH2-5), 2.29-2.33 (2H, m, CH2-9), 2.39 (2H, t, J(H,H)= 7.3 Hz, CH2-12), 3.27-3.33 (2H,

m, CH2-1), 4.52 (2H, s, CH2), 7.27-7.37 (5H, m, ArH); 13C NMR (125 MHz, CDCl3) = 17.1

(CH3), 18.3 (CH2, C9), 20.7 (CH2, C4), 24.0 (CH2, C11), 27.3 (CH2, C10), 33.2 (CH2, C3),

33.4 (CH2, C12), 33.6 (CH, C2), 39.9 (CH2, t, J(C,F)= 26.4 Hz, C5), 73.2 (CH2, Bn), 74.7 (C,

t, J(C,F)= 40.4 Hz, C7), 75.9 (CH2, C1), 87.9 (C, t, J(C,F)= 6.8 Hz, C8), 115.2 (CF2, t,

J(C,F)= 231.2 Hz, C6), 127.7 (CH), 127.8 (CH), 128.6 (CH), 138.7 (C); 19F{1H} NMR (470

MHz, CDCl3) = -80.8 (1F, d, J(F,F)= 267.2 Hz, CFAFB), -81.6 (1F, d, J(F,F)= 267.2 Hz,

CFAFB); 19F NMR (376 MHz, CDCl3) = -81.3 (1F, dtt, J(F,F)= 267.7 Hz, J(H,F)= 14.4, 5.0

Hz, CFAFB), -82.1 (1F, dtt, J(F,F)= 267.7 Hz, J(H,F)= 15.0, 5.0 Hz, CFAFB); MS (ESI) 365

(100) [M-H]¯, 345 (30); HRMS: m/z calcd for C21H27F2O3 [M-H]¯: 365.1934; found:

365.1929.

(12R)-8,8-Difluoro-13-hydroxy-12-methyltridecanoic acid 48

HO13

1211 9

87

6

5 3

21 OH

O

10 4FF

48

A solution of (12R)-13-(benzyloxy)-8,8-difluoro-12-methyltridec-6-ynoic acid 47 (0.12 g,

0.33 mmol, 1.0 eq) and palladium hydroxide (20 wt% on wet carbon, 23 mg, 0.03 mmol, 10

mol%) in THF (20 mL) was stirred under an atmosphere of hydrogen for 20 h. The reaction

mixture was filtered through celite and the celite was washed with THF (30 mL). The THF

layers were combined and the solvent was removed in vacuo. Purification by column

chromatography using silica gel (EtOAc/Pet. ether 1:1) gave (12R)-8,8-difluoro-13-hydroxy-

12-methyltridecanoic acid 48 (42 mg, 46%) as a white solid; mp 67-68 C; [α]D +8.0 (c 0.23,

MeOH); 1H NMR (500 MHz, CDCl3) = 0.94 (3H, d, J(H,H)= 6.7 Hz, CH3), 1.12-1.22 (1H,

m, CH2-11), 1.36-1.69 (13H, m, CH2-3,4,5,6,10,11, CH-12), 1.76-1.85 (4H, m, CH2-7,9),

2.36 (2H, t, J(H,H)= 7.4 Hz, CH2-2), 3.47 (1H, dd, J(H,H)= 10.5, 6.2 Hz, CHAHB-1), 3.52

(1H, dd, J(H,H)= 10.5, 6.0 Hz, CHAHB-1); 13C NMR (125 MHz, CDCl3) = 16.6 (CH3), 20.0

(CH2, t, J(C,F)= 4.5 Hz, C10), 22.3 (CH2, t, J(C,F)= 4.5 Hz, C6), 24.6 (CH2, C3), 28.9 (CH2,

C4/C5), 29.1 (CH2, C4/C5), 33.0 (CH2, C11), 34.0 (CH2, C2), 35.7 (CH, C12), 36.4 (CH2, t,

J(C,F)= 25.5 Hz, C9), 36.7 (CH2, t, J(C,F)= 25.5 Hz, C7), 68.3 (CH2, C13), 125.5 (CF2, t,

J(C,F)= 239.2 Hz, C8), 179.3 (CO2H, C1); 19F{1H} NMR (470 MHz, CDCl3) = -97.7 (2F,

s); 19F NMR (470 MHz, CDCl3) = -97.7 (2F, tt, J(H,F)= 16.6, 16.5 Hz, CF2); MS (ESI) 559

(15) [2M-H]¯, 279 (100) [M-H]¯; HRMS: m/z calcd for C14H25F2O3 [M-H]¯: 279.1777;

found: 279.1773.

(13R)-9,9-Difluoro-13-methyl-1-oxacyclotetradecan-2-one 10

12

13

14

O1

2 3

45

67

8910

11

O

F F

10

Triethylamine (0.29 mL, 2.01 mmol, 15.0 eq) and 2,4,6-trichlorobenzoyl chloride (0.19 mL,

1.34 mmol, 10.0 eq) were added to a solution of (12R)-8,8-difluoro-13-hydroxy-12-

methyltridecanoic acid 48 (38 mg, 0.13 mmol, 1.0 eq) in dry THF (5 mL) at r.t. under argon

and stirred for 2.5 h. The reaction mixture was diluted with dry toluene (20 mL) and added

over 2 h using a syringe pump to a solution of 4-DMAP (0.33 g, 2.68 mmol, 20.0 eq) in dry

toluene (30 mL). The reaction mixture was stirred at r.t. for 18 h. The reaction mixture was

quenched with sat. NaHCO3 solution (50 mL) and extracted with DCM (2 x 50 mL). The

combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4

and the solvent was removed in vacuo. Purification by column chromatography using silica

gel (EtOAc/Pet. ether 1:19) gave (13R)-9,9-difluoro-13-methyl-1-oxacyclotetradecan-2-one

10 (24 mg, 67%) as a white solid; mp 51-53 C; [α]D +5.9 (c 0.59, CHCl3); 1H NMR (500

MHz, CDCl3) = 0.97 (3H, d, J(H,H)= 7.0 Hz, CH3), 1.32-1.52 (10H, m, CH2-5,6,7,11,12),

1.63-1.71 (2H, m, CH2-4), 1.76-1.99 (5H, m, CH-13, CH2-8,10), 2.33-2.45 (2H, m, CH2-3),

3.80 (1H, dd, J(H,H)= 11.2, 7.4 Hz, CHAHB-14), 4.13 (1H, dd, J(H,H)= 11.2, 3.9 Hz,

CHAHB-14); 13C NMR (125 MHz, CDCl3) = 17.7 (CH3), 19.9 (CH2, t, J(C,F)= 5.3 Hz,

C7/C11), 20.2 (CH2, t, J(C,F)= 4.8 Hz, C7/C11), 24.3 (CH2, C4), 26.1 (CH2, C5), 26.5 (CH2,

C6), 31.6 (CH, C13), 32.4 (CH2, t, J(C,F)= 25.7 Hz, C8/C10), 32.6 (CH2, C12), 35.0 (CH2,

C3), 35.1 (CH2, t, J(C,F)= 25.0 Hz, C8/C10), 68.0 (CH2, C14), 126.7 (CF2, J(C,F)= 240.4 Hz,

C9), 174.0 (CO, C2); 19F{1H} NMR (470 MHz, CDCl3) = -90.4 (1F, d, J(F,F)= 243.5 Hz,

CFAFB), -91.0 (1F, d, J(F,F)= 243.5 Hz, CFAFB); 19F NMR (470 MHz, CDCl3) = -90.4 (1F,

dm, J(F,F)= 243.5 Hz, CFAFB), -91.0 (1F, dm, J(F,F)= 243.5 Hz, CFAFB); HRMS: m/z calcd

for C14H28F2N1O3 [M+NH4]+: 280.2083; found: 280.2086

HO

O

19

ON

OO

HOMe

5452

ONH

O

51

a ON

OO

53

b

Me

d

c

OMe

55O

Ph

MeO CF3

Synthesis of Moshers derivative 55. Reagents and conditions: a) (i) 2-Oxazolidinone 51, nBuLi, THF, -78 C,

30 min. (ii) Pivaloyl chloride, NEt3, THF, 0 C, 30 min, r.t., 1.5 h, 50%; b) NaHMDS, MeI, THF, -78 C, 3 h,

34%; c) LiAlH4, Et2O, 0 C, 2 h, 24%; d) (R)-(-)-α-methoxy-α-trifluoromethylphenylacetyl chloride, NEt3, 4-

DMAP, DCM, r.t., 18 h, 78%.

3-(Hex-5-enoyl)-1,3-oxazolidin-2-one 52

ON

OO

52

nBuLi (1.48 M in hexanes, 10.1 mL, 13.8 mmol, 1.2 eq) was added to a solution of 2-

oxazolidinone 51 (1.0 g, 11.5 mmol, 1.0 eq) in dry THF (30 mL) at -78 C under argon. In a

separate flask, pivaloyl chloride (1.8 mL, 15.0 mmol, 1.3 eq) and triethylamine (2.7 mL, 19.6

mmol, 1.7 eq) were added to a solution of hex-5-enoic acid 19 (1.57 g, 13.8 mmol, 1.2 eq) in

dry THF (10 mL) at 0 C under argon and stirred for 30 min. The oxazolidinone solution was

added to the mixed anhydride via cannula and stirred at 0 C for 30 min, then warmed to r.t.

and stirred for 18 h. The reaction mixture was quenched with sat. NH4Cl solution (50 mL)

and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with

sat. NaHCO3 solution (50 mL), sat. NH4Cl solution (50 mL) and brine (50 mL), dried over

anhydrous Na2SO4 and the solvent was removed in vacuo. Purification by column

chromatography (EtOAc 100%) gave 3-(hex-5-enoyl)-1,3-oxazolidin-2-one 52 (1.05 g, 50 %)

as a colourless oil, as a mixture of two regioisomers; 1H NMR (500 MHz, CDCl3) = 1.78

(2H, tt, J(H,H)= 7.5, 7.4 Hz, CH2), 1.78 (2H, tt, J(H,H)= 7.4, 7.2 Hz, CH2), 2.12-2.16 (2H, m,

CH2), 2.93 (2H, t, J(H,H)= 7.5 Hz, CH2), 2.94 (2H, t, J(H,H)= 7.4 Hz, CH2), 4.00-4.04 (2H,

m, CH2), 4.40-4.44 (2H, m, CH2), 4.98-5.07 (2H, m, CH2), 5.77-5.85 (1H, m, CH); 13C NMR

(125 MHz, CDCl3) = 23.6 (CH2), 33.2 (CH2), 34.6 (CH2), 42.7 (CH2), 62.2 (CH2), 115.5

(CH2), 138.0 (CH), 153.7 (CO), 173.6 (CO); MS (ESI) 206 (100) [M+Na]+; HRMS: m/z

calcd for C9H13N1Na1O3 [M+Na]+: 206.0788; found: 206.0781.

3-(2-Methylhex-5-enoyl)-1,3-oxazolidin-2-one 53

ON

OO

53

Me

NaHMDS (1.0 M in THF, 3.0 mL, 3.0 mmol, 1.1 eq) was added to a solution of 3-(hex-5-

enoyl)-1,3-oxazolidin-2-one 52 (0.5 g, 2.7 mmol, 1.0 eq) in dry THF (20 mL) at -78 C under

argon and stirred at -78 C for 1 h. Iodomethane (0.8 mL, 13.5 mmol, 5.0 eq) was added and

the reaction mixture was stirred at -78 C for 1 h, then warmed to r.t. and stirred for 1 h. The

reaction mixture was quenched with sat. NH4Cl solution (50 mL) and extracted with ethyl

acetate (2 x 50 mL). The combined organic layers were washed with sat. NaHCO3 solution

(50 mL), sat. NH4Cl solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and

the solvent was removed in vacuo. Purification by column chromatography (EtOAc/Pet. ether

1:4) gave 3-(2-methylhex-5-enoyl)-1,3-oxazolidin-2-one 53 (0.18 g, 34%) as a colourless oil;

1H NMR (500 MHz, CDCl3) = 1.18 (3H, d, J(H,H)= 6.8 Hz, CH3), 1.47-1.54 (1H, m,

CHAHB), 1.83-1.90 (1H, m, CHAHB), 2.05-2.13 (2H, m, CH2), 3.76 (1H, tq, J(H,H)= 6.9, 6.8

Hz, CH), 4.00-4.04 (2H, m, CH2), 4.39-4.42 (2H, m, CH2), 4.94-5.03 (2H, m, CH2), 5.75-

5.83 (1H, m, CH); 13C NMR (125 MHz, CDCl3) = 17.3 (CH3), 31.6 (CH2), 32.8 (CH2), 37.1

(CH), 43.0 (CH2), 62.0 (CH2), 115.1 (CH2), 138.3 (CH), 153.4 (CO), 177.5 (CO); MS (ESI)

220 (100) [M+Na]+; HRMS: m/z calcd for C10H15N1Na1O3 [M+Na]+: 220.0944; found:

220.0938.

2-Methylhex-5-en-1-ol 54

HOMe

54

Lithium aluminium hydride (0.12 g, 3.2 mmol, 4.0 eq) was added to a solution of 3-(2-

methylhex-5-enoyl)-1,3-oxazolidin-2-one 53 (0.16 g, 0.8 mmol, 1.0 eq) in dry diethyl ether

(10 mL) at 0 C under argon and stirred for 2 h. The reaction mixture was quenched with

water (0.5 mL). Sodium hydroxide solution (2 N, 0.5 mL) was added, followed by water (0.5

mL). The resulting white solid was filtered and the filtrate was collected. The solvent was

removed in vacuo. Purification by column chromatography using silica gel (EtOAc/Pet. ether

1:9) gave 2-methylhex-5-en-1-ol 54 (22 mg, 24%) as a colourless oil. The NMR data was

identical to that reported for (2R)-2-methylhex-5-en-1-ol 23.

2-Methylhex-5-en-1-yl (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate 55

OMe

55O

Ph

MeO CF3

(R)-(-)-α-Methoxy-α-trifluoromethylphenylacetyl chloride (0.03 mL, 0.18 mmol, 2.0 eq) was

added to a solution of 2-methylhex-5-en-1-ol 54 (10 mg, 0.09 mmol, 1.0 eq), triethylamine

(0.02 mL, 0.13 mmol, 1.5 eq) and 4-DMAP (43 mg, 0.35 mmol, 4.0 eq) in dry DCM (1.0

mL) at r.t. and stirred for 18 h. The solvent was removed in vacuo. Purification by column

chromatography using silica gel (Pet. ether 100%) gave 2-methylhex-5-en-1-yl (2R)-3,3,3-

trifluoro-2-methoxy-2-phenylpropanoate 55 (23 mg, 78%) as a colourless oil, as a 1:1

mixture of diastereoisomers; 1H NMR (500 MHz, CDCl3) = 0.94 (3H, d, J(H,H)= 6.7 Hz,

CH3, (R,S)-55), 0.95 (3H, d, J(H,H)= 6.7 Hz, CH3, (R,R)-55), 1.21-1.31 (1H, m, CHAHB),

1.42-1.51 (1H, m, CHAHB), 1.85-1.94 (1H, m, CH), 1.98-2.15 (2H, m, CH2), 3.56 (3H, bq,

J(H,F)= 1.0 Hz, CH3), 4.11 (1H, dd, J(H,H)= 10.8, 6.5 Hz, CHAHB, (R,S-55), 4.16 (1H, dd,

J(H,H)= 10.8, 5.8 Hz, CHAHB, (R,R)-55), 4.20 (1H, dd, J(H,H)= 10.8, 6.5 Hz, CHAHB, (R,S)-

55), 4.25 (1H, dd, J(H,H)= 10.8, 5.6 Hz, CHAHB, (R,R)-55), 4.95-5.03 (2H, m, CH2), 5.71-

5.80 (1H, m, CH), 7.40-7.43 (3H, m, ArH), 7.52-7.53 (2H, m, ArH); 13C NMR (125 MHz,

CDCl3) = 16.8 and 16.8 (CH3), 31.1 (CH2), 32.0 and 32.0 (CH2), 32.3 and 32.4 (CH), 55.6

(CH3), 71.2 and 71.2 (CH2), 115.0 (CH2), 123.6 (q, J(C,F)= 287.9 Hz, CF3), 127.6 (CH),

128.6 (CH x 2), 129.8 (CH), 132.5 (C), 138.4 (C), 166.9 (CO); 19F{1H} NMR (470 MHz,

CDCl3) = -71.54 (3F, s, CF3, (R,S)-55), -71.56 (3F, s, CF3, (R,R)-55); MS (ESI) 683 (15)

[2M+Na]+, 353 (100) [M+Na]+; HRMS: m/z calcd for C17H21F3Na1O3 [M+Na]+: 353.1335;

found: 353.1331.

(2R)-2-Methylhex-5-en-1-yl (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate 56

O

56O

Ph

MeO CF3

(R)-(-)-α-Methoxy-α-trifluoromethylphenylacetyl chloride (0.03 mL, 0.18 mmol, 2.0 eq) was

added to a solution of 2-methylhex-5-en-1-ol 54 (10 mg, 0.09 mmol, 1.0 eq), triethylamine

(0.02 mL, 0.13 mmol, 1.5 eq) and 4-DMAP (43 mg, 0.35 mmol, 4.0 eq) in dry DCM (1.0

mL) at r.t. and stirred for 18 h. The solvent was removed in vacuo. Purification by column

chromatography using silica gel (Pet. ether 100%) gave (2R)-2-Methylhex-5-en-1-yl (2R)-

3,3,3-trifluoro-2-methoxy-2-phenylpropanoate 56 (14 mg, 49%) as a colourless oil; 1H NMR

(500 MHz, CDCl3) = 0.95 (3H, d, J(H,H)= 6.8 Hz, CH3), 1.20-1.30 (1H, m, CHAHB), 1.41-

1.50 (1H, m, CHAHB), 1.83-1.95 (1H, m, CH), 1.98-2.15 (2H, m, CH2), 3.56 (3H, q, J(C,F)=

1.1 Hz, CH3), 4.16 (1H, dd, J(H,H)= 10.7, 5.8 Hz, CHAHB), 4.20 (1H, dd, J(H,H)= 10.7, 6.3

Hz, CHAHB), 4.94-5.03 (2H, m, CH2), 5.70-5.80 (1H, m, CH), 7.40-7.43 (3H, m, ArH), 7.52-

7.54 (2H, m, ArH); 13C NMR (125 MHz, CDCl3) = 16.8 (CH3), 31.1 (CH2), 32.0 (CH2),

32.3 (CH), 55.6 (CH3), 71.2 (CH2), 115.0 (CH2), 123.6 (q, J(C,F)= 287.3 Hz, CF3), 127.5

(CH), 128.6 (CH x 2), 1